WO2015195555A1 - Blocage de cd38 à l'aide d'anticorps anti-cd38 conjugué à la protéine g pour protéger des cellules nk - Google Patents
Blocage de cd38 à l'aide d'anticorps anti-cd38 conjugué à la protéine g pour protéger des cellules nk Download PDFInfo
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- WO2015195555A1 WO2015195555A1 PCT/US2015/035831 US2015035831W WO2015195555A1 WO 2015195555 A1 WO2015195555 A1 WO 2015195555A1 US 2015035831 W US2015035831 W US 2015035831W WO 2015195555 A1 WO2015195555 A1 WO 2015195555A1
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- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
Definitions
- This disclosure relates to methods of protecting natural killer cells from anti-CD38 antibody- induced cell death using an anti-CD38 antibody conjugated to protein G, particularly methods of treating or inhibiting a hyperproliferative disorder in a subject.
- MM Multiple myeloma
- the median overall survival for patients with MM is about 4-7 years, and development of drug resistance is frequent.
- Immunotherapies for MM using anti-CD38 antibodies are in clinical trials and show promise. However, development of additional therapies for MM and other cancers expressing CD38 are still needed to improve patient survival and quality of life.
- an anti-CD38 antibody causes cell death of natural killer (NK) cells by antibody-dependent cell-mediated cytotoxicity (ADCC) through a mechanism involving CD 16.
- ADCC antibody-dependent cell-mediated cytotoxicity
- NK cells are contacted with an anti-CD38 antibody bound or conjugated to protein G (for example, an anti-CD38 antibody-protein G complex) prior to encountering an anti-CD38 antibody and the target cell, the NK cells are protected from anti-CD38 antibody- induced cell death and are available to kill the target cells.
- an anti-CD38 antibody bound or conjugated to protein G for example, an anti-CD38 antibody-protein G complex
- the NK cells are protected from anti-CD38 antibody- induced cell death and are available to kill the target cells.
- NK cells expressing CD38 such as tumor cells or autoimmune disorder-associated cells expressing CD38.
- the methods can include contacting a population of NK cells with a first anti-CD38 antibody bound to protein G (an anti-CD38-protein G complex) to produce a population of NK cells bound to the first anti-CD38 antibody-protein G complex and contacting the CD38-expressing cells with 1) the population of NK cells bound to anti-CD38 antibody-protein G complex and 2) a second anti-CD38 antibody or a fragment thereof, in either order or simultaneously.
- the first anti-CD38 antibody is daratumumab and the second anti-CD38 antibody is daratumumab.
- hyperproliferative disorder including, but not limited to multiple myeloma
- an autoimmune disorder by administering 1) a population of NK cells bound to a first anti-CD38 antibody-protein G complex and 2) a second anti-CD38 antibody (in either order or simultaneously) to a subject having a hyperproliferative disorder or an autoimmune disorder.
- the first anti-CD38 antibody is daratumumab
- the second anti-CD38 antibody is daratumumab.
- compositions that include a population of NK cells bound to an anti-CD38 antibody-protein G complex and a pharmaceutically acceptable carrier.
- the pharmaceutical composition can be used to treat a subject having a hyperproliferative disorder or to decrease growth or proliferation of cells expressing CD38, for example utilizing the methods disclosed herein.
- FIG. 1 is a plot showing expression of CD38 on T cells, NK cells, B cells, and myeloma cells.
- FIGS. 2A and 2B are graphs showing the effect of activation and expansion on CD38 expression on NK cells.
- FIG. 2A is a flow cytometry plot and FIG. 2B is a bar graph showing CD38 expression in fresh NK cells, NK cells treated with IL-2 for 18 hours, and NK cells expanded for 7 days in IL-2 containing media on EBV-LCL feeder cells.
- FIGS. 3A-3C are a series of panels showing NK cell viability (measured by Annexin V) in control NK cells (FIG. 3A) or in NK cells incubated with 1 ⁇ g/ml daratumumab (FIG. 3B) or 10 ⁇ g/ml daratumumab (FIG. 3C).
- FIGS. 4A and 4B are a series of panels showing CD16 and CD38 expression in expanded NK cells .
- FIG. 4A shows CD 16 + NK cells and
- FIG. 4B shows CD 16 " NK cells .
- FIGS. 5 A and 5B are a series of panels showing the effect of daratumumab on CD 16 " (FIG. 5 A) or CD16 + (FIG. 5B) NK cell viability in control cells (left panels), 10 ⁇ g/ml daratumumab- treated cells (middle panels), and 100 ⁇ g/ml daratumumab-treated cells (right panels).
- FIGS. 6A-6C are a series of graphs showing % lysis of tumor cell lines in a four hour co- culture of NK cells with 1 ⁇ g/ml or 10 ⁇ g/ml daratumumab or control cells.
- FIG. 6A shows K562 tumor cells;
- FIG. 6B shows MM1S tumor cells;
- FIG. 6C shows OPM1 tumor cells.
- FIGS. 7A-7C are a series of graphs showing % lysis of tumor cells when daratumumab is added to the tumor cells at 1 ⁇ g/ml or 10 ⁇ g/ml then washed off, followed by four hour co-culture with NK cells. Control represents no daratumumab added to the tumor cells.
- FIG. 7A shows K562 tumor cells;
- FIG. 7B shows MM1S tumor cells;
- FIG. 7C shows OPM1 tumor cells.
- FIGS. 8 A and 8B are a series of panels showing expression of CD38 in NK cells from two donors with low affinity CD16 genotype. Left panels show CD38 staining on NK cells from both donors and right panels show CD38 staining on NK cells from both donors when NK cells have been pretreated with daratumumab at 10 ⁇ g/ml.
- FIG. 8 A shows donor 1 (D64) and FIG. 8B shows Donor 2 (D136).
- FIGS. 9 A and 9B are a series of panels showing expression of CD38 in NK cells from two donors with high affinity CD16 genotype. Left panels show CD38 expression on NK cells from both donors and right panels show CD38 expression on NK cells from both donors when NK cells have been pretreated with daratumumab at 10 ⁇ g/ml.
- FIG. 9A shows donor 3 (D09) and FIG. 9B shows Donor 4 (D96).
- FIGS. 10A and 10B are a series of panels showing the effect of daratumumab on CD 16 " (FIG. 10A) or CD16 + (FIG. 10B) NK cell viability in high affinity CD 16 genotype NK cells (D96) with or without (control) daratumumab treatment.
- FIGS. 11A and 1 IB are graphs showing U226 myeloma cell lysis by low affinity CD 16 NK cells (FIG. 11A) or high affinity CD16 NK cells (FIG. 1 IB) when tumor cells are cultured with daratumumab alone, NK cells alone, or NK cells and daratumumab.
- FIG. 12 is a graph showing fold increase in myeloma cell lysis by low or high affinity CD16 NK cells with daratumumab vs. NK cell killing alone without daratumumab.
- FIGS. 13A-13C are a series of panels showing effect of daratumumab on low affinity CD 16 (FcyRIII) NK cell (NK0136) viability in control cells (FIG. 13 A), cells treated with protein G- bound daratumumab (FIG. 13B), or cells treated with protein G alone (FIG. 13C).
- FIGS. 14A-14C are a series of panels showing effect of daratumumab on high affinity CD16 NK cell (NK1096) viability in control cells (FIG.14 A) cells, cells treated with protein G alone (FIG. 14B), or cells treated with protein G-bound daratumumab (FIG. 14C)
- FIG. 15 is a series of panels showing effect of daratumumab on low affinity CD 16 NK cell (NK0136) viability in control cells (left), cells treated with protein G alone (middle panels), or cells treated with protein G-bound daratumumab (right panels).
- FIGS. 16A and 16B are schematic diagrams showing binding of protein G to daratumumab
- FIG. 16 A the proposed effect of protein G-bound daratumumab on apoptosis of NK cells via daratumumab (FGI. 16B).
- FGI. 16B the proposed effect of protein G-bound daratumumab on apoptosis of NK cells via daratumumab.
- Preventing apoptosis of NK cells by daratumumab is believed to augment apoptosis of tumor cells by the NK cells.
- FIGS. 17 A and 17B are a pair of graphs showing interferon ⁇ (IFNy) secretion level in CD16 + NK cells but not in CD16 " NK cells after treatment with daratumumab.
- K562 cancer cell line was used as a target tumor.
- NK cells from two different donors NK1096, FIG. 17A and NK0136, FIG. 17B were tested.
- FIGS. 18A and 18B are a pair of graphs showing IFNy secretion by NK1096 NK cells (FIG. 18 A) or NK0136 NK cells (FIG. 18B) treated with daratumumab vs. control untreated cells, cells treated with protein G alone, and cells treated with protein G-bound daratumumab (PG-DARA) in response to K562 cell line.
- NK1096 NK cells FIG. 18 A
- PG-DARA protein G-bound daratumumab
- FIGS. 19A and 19B are a pair of graphs showing IFNy secretion by NK1096 NK cells (FIG. 19A) or NK0136 NK cells (FIG. 19B) treated with protein G-bound daratumumab in response to tumor cell lines K562 and Raji.
- Antibody A protein (or protein complex) that includes one or more polypeptides substantially encoded by immunoglobulin genes or fragments of immunoglobulin genes.
- the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad of immunoglobulin variable region genes.
- Light chains are classified as either kappa or lambda.
- Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
- the basic immunoglobulin (antibody) structural unit is generally a tetramer.
- Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kDa) and one "heavy” (about 50-70 kDa) chain.
- the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
- the terms "variable light chain” (V L ) and “variable heavy chain” (V H ) refer, respectively, to these light and heavy chains.
- antibodies includes intact immunoglobulins as well as a number of well-characterized fragments. For instance, Fabs, Fvs, and single-chain Fvs (scFvs) that bind to target protein (or epitope within a protein or fusion protein) would also be specific binding agents for that protein (or epitope).
- antibody fragments are defined as follows: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab', the fragment of an antibody molecule obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab' fragments are obtained per antibody molecule; (3) (Fab') 2 , the fragment of the antibody obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; (4) F(ab') 2 , a dimer of two Fab' fragments held together by two disulfide bonds; (5) Fv, a genetically engineered fragment containing the variable region of the light chain and the variable region of the heavy chain expressed as two chains; and (6) single chain antibody, a genetically engineered molecule containing the variable region of the light chain, the variable region of the heavy chain, linked by a suitable polypeptide linker as a genetic
- Binding/stable binding An association between two substances or molecules, such as the association of an antibody or an antibody fragment with a polypeptide.
- An antibody binds or stably binds a target protein ⁇ e.g., CD38) when a sufficient amount of the antibody or antibody fragment binds to its target protein to permit detection of that binding.
- Binding can be detected by any procedure known to one skilled in the art, such as by physical or functional properties of the target: antibody complex. Physical methods of detecting the binding of a target protein to an antibody or antibody fragment, include but are not limited to, such methods as Western blotting, immunohistochemistry, flow cytometry, or other methods known to one of skill in the art.
- CD16 Also known as Fc fragment of IgG, low affinity Ilia, receptor (FcyRIIIA).
- CD16 is a receptor for the Fc portion of immunoglobulin G, which is involved in antibody-dependent responses, and also removing antigen-antibody complexes from the circulation.
- CD16 is expressed on most NK cells as a transmembrane glycoprotein. About 90% of NK cells express CD16, while about 10% do not express CD16 or express low amounts of CD16.
- Exemplary human CD16 sequences include GenBank Accession Nos.
- NM_001127596, NM_001127595, NM_001127593, NM_001127592, and NM_000569 nucleic acid sequences
- NP_001121068, NP_001121067, NP_001121065, NP_001121064, and NP_000560 amino acid sequences
- a CD16 positive (CD16 + ) cell (also referred to herein as a CD16-expressing cell) is a cell that expresses a detectable amount of CD 16 protein (for example, using flow cytometry).
- CD38 Also known as T10 or ADPRC1.
- the CD38 molecule is a type II transmembrane glycoprotein with a molecular weight of approximately 45 kD. It is a bifunctional ectoenzyme, capable of catalyzing conversion of nicotinamide adenine dinucleotide (NAD+) to cyclic ADP- ribose (cADPR) and conversion of cADPR into ADP-ribose.
- CD38 is also involved in cell adhesion and cellular signaling, including calcium mobilization.
- Exemplary human CD38 sequences include GenBank Accession Nos. NM_001775 (nucleic acid sequence) and NP_001766 (amino acid sequence), both of which are incorporated herein by reference as present in GenBank on June 16, 2014.
- a CD38 positive (CD38+) cell (also referred to herein as a CD38-expressing cell) is a cell that expresses a detectable amount of CD38 protein (for example, using flow cytometry).
- a cell expressing an increased amount of CD38 compared to a control sample or reference value is referred to as over-expressing CD38.
- a first unit coupled to or bound to a second unit is a complex. This includes, but is not limited to, covalently bonding one molecule to another molecule (for example, directly or via a linker molecule), noncovalently bonding one molecule to another (e.g. electrostatically bonding), non-covalently bonding one molecule to another molecule by hydrogen bonding, noncovalently bonding one molecule to another molecule by van der Waals forces, and any and all combinations of such couplings.
- a complex includes an anti-CD38 antibody bound to protein G, for example, through the natural affinity of protein G for immunoglobulins.
- Contacting Placement in direct physical association, including both a solid and liquid form. Contacting can occur in vitro or ex vivo with isolated cells or tissue or in vivo by
- Daratumumab A human CD38 monoclonal antibody (also known as HUMAX®-CD38). See, e.g., de Weers et al, J. Immunol. 186: 1840-1848, 2011; U.S. Pat. No. 7,829,673.
- Daratumumab exhibits cytotoxic activity through several mechanisms, including ADCC, CDC, and apoptosis. In ongoing clinical trials, daratumumab has exhibited positive effects against multiple myeloma.
- Effective amount An amount of a preparation that alone, or together with a
- a therapeutic agent or preparation such as an antibody or antibody fragment, or a preparation of cells bound to an antibody or antibody fragment, is administered in therapeutically effective amounts.
- Effective amounts a therapeutic agent can be determined in many different ways, such as assaying for a reduction in symptoms or improvement of physiological condition of a subject having a disorder (such as a hyperproliferative disorder). Effective amounts also can be determined through various in vitro, in vivo, or in situ assays.
- Hyperproliferative disorder Any of a number of diseases that are characterized by uncontrolled, abnormal proliferation of cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other parts of the body (for example,
- a hyperproliferative disorder includes a tumor (such as a benign or malignant tumor) or a hematological malignancy (such as a leukemia or lymphoma).
- Isolated An "isolated" biological component (such as a nucleic acid molecule, protein, or cell) has been substantially separated or purified away from other biological components in the preparation, cell, or organism in which the component is present, such as other chromosomal and extra-chromosomal DNA and RNA, proteins and cells. Proteins (such as antibodies or antibody fragments) that have been "isolated” include proteins purified by standard purification methods. The term also embraces proteins prepared by recombinant expression in a host cell as well as chemically synthesized proteins. An isolated cell can be an NK cell that is substantially separated from other cell subtypes.
- NK cells A form of lymphocyte that is a component of the innate immune system. NK cells are cytotoxic to target cells, including tumor cells and virally infected cells. In some examples, NK cells recognize cells with surface-bound antibodies via CD16 (FyRIII), resulting in activation of the NK cells and release of cytolytic granules, leading to apoptosis of the target cell.
- CD16 CD16
- NK cells are CD37CD56 "1" cells that typically make up about 5-15% of circulating lymphocytes. They are further divided into two sub-populations based on the level of CD56 expression and whether they are positive or negative for CD16 (e.g., CD56 CD16 + and CD56 bright CD16 " ). The CD16 + sub-population makes up about 90% of the total NK cell population.
- compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions are conventional.
- Remington The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005), describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions.
- the nature of the carrier will depend on the particular mode of administration being employed.
- parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
- non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
- Protein G An immunoglobulin binding protein from streptococcal bacteria. Protein G is an approximately 32 kDa protein that binds primarily to the Fc region of IgGs from most species, including human IgG. Purified or recombinant protein G is commercially available, for example from Sigma- Aldrich (St. Louis, MO), Pierce (Thermo Fisher Scientific, Rockford, IL), Life Technologies (Carlsbad, CA), and others.
- purified does not require absolute purity; rather, it is intended as a relative term.
- a purified protein preparation is one in which the protein referred to is more pure than the protein in its environment (such as within a cell).
- a preparation of a protein is purified such that the protein represents at least 50% (for example, at least 70%, 80%, 90%, 95%, 98%, or more) of the total protein content of the preparation.
- a purified population of cells is one in which the cells referred to (such as NK cells) is more pure than the cells in their natural environment in an organism, for example, the cell type represents at least 50% (for example, at least 70%, 80%, 90%, 95%, 98%, or more) of the total cell content of the preparation.
- Subject Living multi-cellular vertebrate organisms, a category that includes human and non-human mammals.
- Treating or inhibiting refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition (such as a
- Inhibiting refers to inhibiting the full development of a disease. Inhibition of a disease can span the spectrum from partial inhibition to substantially complete inhibition (e.g., including, but not limited to prevention) of the disease. In some examples, the term “inhibiting” refers to reducing or delaying the onset or progression of a disease.
- a subject to be treated, such as with the methods disclosed herein, can be identified by standard diagnosing techniques for such a disorder, for example, symptoms, basis of family history, or risk factors to develop the disease or disorder.
- Tumor A neoplasm that may be either malignant or non-malignant (benign).
- Tumors of the same tissue type are tumors originating in a particular organ (such as brain, breast, lung, or colon) or cell type (such as glial cell, for example astrocyte or oligodendrocyte).
- Tumors include original (primary) tumors, recurrent tumors, and metastases (secondary tumors).
- a tumor recurrence is the return of a tumor, at the same site (for example, in the same organ or tissue) as the original (primary) tumor, after the tumor has been removed surgically, by drug or other treatment, or has otherwise disappeared.
- a metastasis is the spread of a tumor from one part of the body to another. Tumors formed from cells that have spread are called secondary tumors (or metastatic tumors) and contain cells that are like those in the original (primary) tumor. There can be a recurrence of either a primary tumor or a metastas
- NK cells expressing CD38 such as tumor cells or autoimmune cells expressing CD38
- methods of inhibiting growth or proliferation of cells expressing CD38 by contacting the CD38-expressing cells with 1) NK cells bound to an anti-CD38 antibody bound to (for example, complexed with or conjugated with) protein G and 2) an anti-CD38 antibody (such as an intact anti- CD38 antibody), in either order or simultaneously.
- the methods provided herein inhibit growth or proliferation of CD38-expressing cells (for example solid tumor or hematological malignancy cells that express CD38).
- the methods can include contacting a population of NK cells (for example CD16 + NK cells) with a first anti-CD38 antibody-protein G complex.
- the NK cells are contacted with about 1 ⁇ to 1 mg anti-CD38 antibody-protein G complex (such as about 1-10 ⁇ g, about 5-50 ⁇ g, about 10- 100 ⁇ g, about 25-500 ⁇ g, or about 50- 1000 ⁇ g, for example, about 2 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, or more) for a period of time sufficient to produce a population of NK cells bound to the anti-CD38 antibody- protein G complex (for example for about 5 minutes to about 4 hours) at 4°C to 37°C (such as room temperature, in some examples).
- about 1 ⁇ to 1 mg anti-CD38 antibody-protein G complex such as about 1-10 ⁇ g, about 5-50 ⁇ g, about 10- 100 ⁇ g, about 25-500 ⁇ g, or about 50- 1000 ⁇ g, for example, about 2 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 25 ⁇
- the NK cells are contacted with the anti- CD38 antibody-protein G complex in vitro or ex vivo, for example, following isolation of NK cells from a sample from a subject.
- the population of NK cells is contacted with a protein G bound anti- CD38 antibody (such as daratumumab) in vitro or ex vivo.
- the amount of anti-CD38 antibody- protein G complex used is an amount sufficient to produce stable binding to CD38 present on the NK cells.
- the amount of anti-CD38 antibody-protein G complex added is an amount sufficient to bind at least 50% (for example, at least 60%, 70%, 75%, 80%, 90%, 95%, or even 100%) of the CD38 epitopes present on the NK cells.
- the anti-CD38 antibody were to be subsequently added to these NK cells it would not be able to substantially bind CD38 present on the NK cell surface, as the CD38 epitopes would be bound by theanit-CD38 antibody-protein G complex.
- the NK cells may be expanded prior to contacting the population of NK cells with the anti-
- NK cells their optional expansion, and contacting a population of NK cells with an anti-CD38 antibody-protein G complex to produce a population of NK cells bound to the anti-CD38 antibody-protein G complex are described in greater detail in Section V, below.
- the methods further include producing a complex of an anti-CD38 antibody and protein G.
- the complex is produced by contacting an anti-CD38 antibody with protein G, for example in a solution (such as phosphate buffered saline).
- the anti-CD38 antibody is contacted with about 1 ⁇ g to 1 mg protein G (such as about 1-10 ⁇ g, about 5-50 ⁇ g, about 10-100 ⁇ g, about 25-500 ⁇ g, or about 50-1000 ⁇ g, for example, about 2 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, or more) for a sufficient time for the protein G to bind to the Fc portion of the anti-CD38 antibody and form a complex (for example about 5 minutes to 2 hours).
- an excess of anti-CD38 antibody is used to form the complex with protein G (such as about 2: 1, about 3: 1, about 5: 1, about 10: 1 ratio or more of antibody to protein G). In other examples, a ratio of less than 2: 1 of antibody to protein G is used, for example, about 1.5:1, about 1: 1, about 0.75: 1, or less.
- the population of NK cells bound to the first anti-CD38 antibody-protein G complex is then contacted with one or more cells expressing CD38 (such as a population of cells, for example a population of tumor cells) and a second anti-CD38 antibody.
- the CD38- expressing cells are contacted with about 0.01 ⁇ g/ml to about 1 mg/ml (such as about 0.1-1 g/ml, about 0.5-10 ⁇ g/ml, about 1-25 ⁇ g/ml, about 5-50 ⁇ g/ml, about 10-100 ⁇ g/ml, about 25-500 ⁇ g/ml, for example, about 0.05 ⁇ g/ml, about 1 ⁇ g/ml, about 5 ⁇ g/ml, about 10 ⁇ g/ml, about 25 ⁇ g/ml, about 50 ⁇ g/ml, about 100 ⁇ g/ml, about 250 ⁇ g/ml, about 500 ⁇ g/ml, or more) of the second anti- CD38 antibody.
- the CD38 expressing cell (which in some examples is not a NK cell) is contacted with the population of NK cells bound to the first anti-CD38 antibody-protein G complex and the second CD38 antibody sequentially, substantially simultaneously, or simultaneously.
- the CD38 expressing cell is contacted with the second anti-CD38 antibody prior to being contacted with the population of NK cells bound to the first anti-CD38 antibody-protein G complex.
- the CD38 expressing cell is contacted with the second anti-CD38 antibody at least 1 hour to 48 hours (for example, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 18 hours, about 24 hours, or about 36 hours) before contacting the cells with the population of NK cells bound to the first anti-CD38 antibody-protein G complex.
- the step of contacting the CD38-expressing cell(s) with the population of NK cells bound to the first anti-CD38 antibody-protein G complex occurs in vitro or ex vivo. In other examples, the step of contacting the CD38-expressing cell(s) with the population of NK cells bound to the first anti-CD38 antibody-protein G complex occurs in vivo, for example, by administering the population of NK cells bound to the first anti-CD38 antibody-protein G complex to a subject (such as a subject with a hyperproliferative disorder). In such in vivo methods, the second anti-CD38 antibody is also administered to the subject, before, after, or substantially simultaneously with administration of the population of NK cells bound to the first anti-CD38 antibody-protein G complex.
- the second anti-CD38 antibody is administered to the subject at least 1 hour to one week (for example, about 2 hours, about 12 hours, about 24 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days) before administering the population of NK cells bound to the first anti-CD38 antibody- protein G complex.
- the population of NK cells may be autologous NK cells, for example, NK cells that have been isolated from the same subject and contacted with the first anti-CD38 antibody- protein G complex ex vivo. These NK cells may be collected and bound by anti-CD38 antibody- protein G complex immediately after collection, following ex vivo activation with cytokines, or following ex vivo expansion/culturing before they are administered to the subject.
- the first and second anti-CD38 antibodies are the same antibody. In other examples, the first anti-CD38 antibody and the second anti-CD38 antibody are different. In particular example, the anti-CD38 antibodies are human or humanized antibodies. Anti-CD38 antibodies for use in the methods disclosed herein are discussed in Section IV below. In one non- limiting example, the first and second antibodies are daratumumab. Methods of assessing the growth or proliferation of cells include determining cell number, for example before and after contacting the CD38-expressing cells with the population of NK cells bound to the first anti-CD38 antibody-protein G complex and the second anti-CD38 antibody.
- a decrease (or no statistically significant increase) in the number of the CD38-expressing cells after treatment indicates that the growth or proliferation of the cells has been inhibited.
- Methods of determining cell number include counting the number of cells, for example by visualizing the cells, using a Coulter counter, or by flow cytometry. Growth or proliferation of cells can also be determined using cell viability assays (for example using fluorescent DNA binding dyes such as 7- aminoactinomycin D or tetrazolium reduction assays), or by determining the number of apoptotic or dead cells (for example, by flow cytometry (for example, detecting Annexin V), TUNEL assay, LDH assay, measuring intracellular caspases, or 51 Cr release assay).
- the number, viability, or amount of cell death can be determined in a sample from the subject (for example in a tumor sample or a blood sample from the subject), by imaging studies (such as CT scan, PET/CT scan, MRI, skeletal series, or bone scan), or by assessment of tumor size by physical examination.
- imaging studies such as CT scan, PET/CT scan, MRI, skeletal series, or bone scan
- the methods provided herein treat or inhibit a hyperproliferative disorder in a subject (for example a subject with a solid tumor or hematological malignancy cells).
- the methods include administering to the subject an effective amount (such as a therapeutically effective amount) of a population of NK cells bound to a first anti-CD38 antibody-protein G complex and administering to the subject an effective amount (such as a therapeutically effective amount) of a second anti-CD38 antibody.
- the second anti-CD38 antibody is administered to the subject before, after, or substantially simultaneously with the population of NK cells bound to the first antibody-protein G complex.
- the subject is administered the second anti- CD38 antibody at least about 1 hour to three weeks (for example, about 2 hours, about 12 hours, about 24 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 14 days, or about 21 days) before administration of the population of NK cells bound to the first anti-CD38 antibody-protein G complex.
- the subject has a solid tumor or hematological malignancy that expresses CD38. Dosing, routes of administration and timing of administration are described in further detail in Section VI, below.
- the population of NK cells bound to the first anti-CD38 antibody-protein G complex is produced by contacting NK cells (for example CD16 + NK cells) with a complex of the first anti- CD38 antibody and protein G for a period of time sufficient to produce a population of NK cells bound to the antibody-protein G complex (for example for about 10 minutes to about 2 hours).
- NK cells for example CD16 + NK cells
- the NK cells are contacted with the anti-CD38 antibody-protein G complex in vitro or ex vivo, for example, following isolation of NK cells from a sample from a subject.
- the NK cells may be collected and bound by anti-CD38-protein G complex immediately after collection, following ex vivo activation with cytokines, or following ex vivo expansion/culturing.
- the population of NK cells may be autologous NK cells, for example, NK cells that have been isolated from the same subject and contacted with the anti-CD38 antibody-protein G complex ex vivo.
- the NK cells may be allogeneic. Allogeneic NK cells may be from a related or unrelated donor and may be either partially or fully HLA-matched.
- NK cells, their optional expansion, and contacting a population of NK cells with a complex of an anti-CD38 antibody and protein G to produce a population of NK cells bound to the antibody-protein G complex are described in greater detail in Section V, below.
- the methods further include producing a complex of an anti-CD38 antibody and protein G.
- the complex is produced by contacting an anti-CD38 antibody with protein G, for example in a solution (such as phosphate buffered saline).
- the anti-CD38 antibody is contacted with about 1 ⁇ g to 1 mg protein G (such as about 1-10 ⁇ g, about 5-50 ⁇ g, about 10-100 ⁇ g, about 25-500 ⁇ g, or about 50-1000 ⁇ g, for example, about 2 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, about 500 ⁇ g, or more) for a sufficient time for the protein G to bind to the Fc portion of the anti-CD38 antibody and form a complex (for example about 5 minutes to 2 hours).
- an excess of anti-CD38 antibody is used to form the complex with protein G (such as about 2: 1, about 3: 1, about 5: 1, about 10: 1 ratio or more of antibody to protein G). In other examples, a ratio of less than 2: 1 of antibody to protein G is used, for example, about 1.5:1, about 1: 1, about 0.75: 1, or less.
- the first and second anti-CD38 antibodies are the same antibody. In other examples, the first anti-CD38 and the second anti-CD38 antibody are different. In particular example, the anti-CD38 antibodies are human antibodies. Anti-CD38 antibodies for use in the methods disclosed herein are discussed in Section IV below. In one non-limiting example, the first and second antibodies are daratumumab. C. Pharmaceutical Compositions
- compositions comprising a population of NK cells bound to an anti-CD38 antibody-protein G complex and a pharmaceutically acceptable carrier.
- anti-CD38 antibody is a human, humanized, or chimeric anti-CD38 antibody.
- the antibody is daratumumab; however, any anti-CD38 antibody can be used.
- the composition includes about 10 4 to 10 11 NK cells bound to an anti- CD38 antibody-protein G complex.
- the composition may be prepared such that about 10 6 to 10 9 NK cells/kg are administered to a subject.
- compositions include pharmaceutically acceptable carriers and/or one or more additional agents.
- additional agents include pharmaceutically acceptable carriers and/or one or more additional agents.
- Actual methods for preparing administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005).
- the composition may be prepared by contacting a population of NK cells with an anti- CD38 antibody-protein G complex for a period of time sufficient to produce a population of NK cells bound to the antibody-protein G complex (for example, as described in Section V).
- the NK cells bound to the anti-CD38 antibody-protein G complex may be washed (for example, to remove culture medium (if present), unbound antibody-protein G complex, or other components).
- the NK cells are then resuspended in a pharmaceutically acceptable carrier, which may include additional preservatives, surfactants, or other therapeutic agents.
- the composition is stored (for example, at -20°C or -80°C) until use.
- NK cells are frozen after collection and optional ex vivo activation or expansion, and are later thawed and contacted with an anti-CD38 antibody-protein G complex prior to administration to a subject.
- the CD38 molecule is a type II transmembrane glycoprotein with a molecular weight of approximately 45 kD. It is a bifunctional ectoenzyme, capable of catalyzing conversion of nicotinamide adenine dinucleotide (NAD + ) to cyclic ADP-ribose (cADPR) and conversion of cADPR into ADP-ribose. CD38 is also involved in cell adhesion and cellular signaling, including calcium mobilization.
- CD38 is expressed by hematopoietic cells, including medullary thymocytes, activated T and B cells, NK cells, monocytes, lymph node germinal center lymphoblasts, plasma B cells, and it can also be expressed by dendritic cells. Many normal bone marrow cells, including precursor cells, also express CD38. In addition to hematopoietic cells, CD38 is also expressed on intra-epithelial cells and lamina intestinal cells in the gut, Purkinje cells, pancreatic ⁇ -cells, prostate epithelial cells, osteoclasts, retinal cells, and muscle. Exemplary human CD38 sequences include GenBank Accession Nos. NM_001775 (nucleic acid sequence) and NP_001766 (amino acid sequence), both of which are incorporated herein by reference as present in GenBank on June 16, 2014.
- CD38 expression is up-regulated in hematological malignancies, including but not limited to multiple myeloma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, pro-lymphocytic/myelocytic leukemia, plasma cell leukemia, NK cell leukemia, Waldenstrom macroglobulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma.
- Increased expression of CD38 may also occur in solid tumors, including but not limited to colorectal tumors, lung carcinoma, prostate cancer, pancreatic cancer (for example, insulinoma), breast cancer, neuroblastoma, testicular cancer (such as seminoma), and ovarian cancer.
- solid tumors including but not limited to colorectal tumors, lung carcinoma, prostate cancer, pancreatic cancer (for example, insulinoma), breast cancer, neuroblastoma, testicular cancer (such as seminoma), and ovarian cancer.
- anti-CD38 monoclonal antibodies can affect the viability and growth of tumor cells. These antibodies have been shown to mediate killing of CD38 + tumor cells by CDC, ADCC, and/or apoptosis. Two anti-CD38 monoclonal antibodies, daratumumab and SAR650984, are currently in clinical trials for treatment of multiple myeloma and have shown promising results.
- the presently disclosed methods utilize antibodies or antigen binding fragments thereof that specifically or stably bind CD38.
- the antibody is a monoclonal antibody.
- the antibody can be a fully human, humanized, or a chimeric antibody.
- other antibody forms, such as camelids can be used in the methods disclosed herein.
- these antibodies specifically or stably bind CD38.
- the antibodies used in the methods disclosed herein are human antibodies.
- Antibodies that specifically or stably bind CD38 are commercially available and are known in the art. For example, antibodies that bind human CD38 are disclosed in U.S. Patent Nos.
- Such antibodies include antibodies (and antigen binding fragments derived from the antibodies) known as daratumumab (also known as HuMax®-CD38; Genmab, Princeton, NJ; de Weers et al, J. Immunol. 186: 1840-1848, 2011; U.S. Pat. No. 7,829,673) and SAR650984 (Sanofi, Bridgewater, NJ; U.S. Pat. Nos. 8,153,765; 2011/0262454).
- daratumumab also known as HuMax®-CD38; Genmab, Princeton, NJ; de Weers et al, J. Immunol. 186: 1840-1848, 2011; U.S. Pat. No. 7,829,673
- SAR650984 Sanofi, Bridgewater, NJ; U.S. Pat. Nos. 8,153,765; 2011/0262454
- Additional antibodies that bind CD38 include for example, OKT10 (Stevenson et al, Blood 77:1071-1079, 1991), AT13/5 (U.S. Pat. App. Publ. No. 2002/0164788), IB4 (Zupo et al, Eur. J. Immunol. 24: 12180111, 1994; Morra et al, FASEB J. 12:581-592, 1998), T16 (Kumagai et al, J. Exp. Med. 1101-1110, 1995; Todisco et al, Blood 95:535-542, 2000), and antibodies described in WO 2005/103083.
- OKT10 Stevenson et al, Blood 77:1071-1079, 1991
- AT13/5 U.S. Pat. App. Publ. No. 2002/0164788
- IB4 Zaupo et al, Eur. J. Immunol. 24: 12180111, 1994; Morra et al, FASEB J
- the antibody that specifically binds CD38 is daratumumab.
- Daratumumab is a human monoclonal antibody that specifically binds CD38 (e.g., U.S. Pat. No. 7,829,673).
- Daratumumab binds to an epitope on human CD38 that includes amino acids 233-246 and 267-280, of which serine 274 has been identified as particularly important for antibody binding (de Weers et ah, J. Immunol. 186: 1840-188, 2011).
- the methods disclosed herein utilize daratumumab bound to or complexed with protein G (for example, for pre-treatment of NK cells). In other embodiments, the methods disclosed herein utilize daratumumab (for example, for administration to a subject alone or in conjunction with NK cells pre-treated with an anti-CD38 antibody-protein G complex). In still further embodiments, the methods utilize both fragments of daratumumab and intact daratumumab.
- NK cells are non-T, non-B lymphocytes with intracellular granules that are a component of the innate immune system. They are the effectors in ADCC that can kill sensitive targets, including tumor cells and virally infected cells. ADCC is triggered when receptors on the NK cell surface (such as CD 16) recognize IgGl or IgG3 antibodies bound to the surface of a cell. This triggers release of cytoplasmic granules containing perforin and granzymes, leading to cell death.
- NK cells are CD37CD56 "1" cells that typically make up about 5-15% of circulating lymphocytes. They are further divided into two sub-populations based on the level of CD56 expression and whether they are positive or negative for CD16 (e.g., CD56 dim CD16 + and
- CD56 bright CD16 " The CD16 + sub-population makes up about 90% of the total NK cell population.
- a population of NK cells is contacted with a previously prepared complex of an anti-CD38 antibody and protein G to produce a population of NK cells bound to the antibody-protein G complex.
- the population of NK cells is contacted with the anti-CD38 antibody and protein G separately (for example, sequentially or substantially simultaneously).
- the population of NK cells is an isolated or purified population of NK cells, such as a preparation that is at least 70% (such as at least 80%, 90%, 95%, 98%, 99%, or more) NK cells, for example a preparation that is substantially free of cells other than NK cells.
- the NK cell population is substantially free of B cells and/or T cells.
- a population of NK cells for use in the disclosed methods can be obtained by any means known to one of skill in the art or developed in the future.
- the NK cells may be collected and bound by anti-CD38 antibody-protein G complex immediately after collection, following ex vivo activation with cytokines, or following ex vivo expansion/culturing.
- the NK cells are cultured ex vivo for up to 42 days following collection.
- NK cells are isolated from a blood sample by depleting the sample of CD3 + cells. In some examples, following CD3 + depletion, the remaining cells are selected for CD56 + cells and/or depleted of CD19 + cells. In other examples, NK cells are isolated by a negative NK cell depletion method, for example which depletes the sample of CD3 + T-cells and other non- NK cell populations such as B cells and myeloid cells. In some examples, the sample is also selected for CD16 + cells, to produce a population of CD16 + NK cells. The NK cell population can be selected for the presence or absence of particular cell surface markers such as CD3, CD56, CD 19 and/or CD 16 by methods known to one of skill in the art, for example using flow cytometry techniques.
- the population of NK cells is contacted with an anti-CD38 antibody (such as a
- the amount of the antibody-protein G complex used is an amount sufficient to produce stable binding to CD38 present on the NK cells.
- the amount of antibody-protein G complex added is an amount sufficient to bind at least 50% (for example, at least 60%, 70%, 75%, 80%, 90%, 95%, or even 100%) of the CD38 epitopes present on the NK cells.
- the anti-CD38 antibody were to be subsequently added to these NK cells it would not be able to substantially bind CD38 present on the NK cell surface, as the CD38 epitopes would be bound by the anti-CD38 antibody-protein G complexes.
- the population of NK cells is contacted with about 0.1 ⁇ g to about 200 ⁇ g (such as about 0.1-25 ⁇ g, about 0.5-50 ⁇ g, about 1-10 ⁇ g, about 5-25 ⁇ g, about 10-100 ⁇ g, about 25-200 ⁇ g, for example, about 1 ⁇ g, about 2 ⁇ g, about 5 ⁇ g, about 10 ⁇ g, about 25 ⁇ g, about 50 ⁇ g, about 100 ⁇ g, or about 200 ⁇ g) of the antibody-protein G complex.
- the NK cells may be contacted with about 1 ⁇ g to about 200 ⁇ g antibody-protein G complex per 10 8 NK cells.
- the NK cells are contacted with the anti-CD38 antibody-protein G complex for a period of time sufficient to produce stable binding of the anti-CD38 antibody-protein G complex to the NK cells, for example at least about 5 minutes to 4 hours (such as about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, or about 4 hours).
- the NK cells are contacted with the antibody-protein G complex in a suitable medium, such as an NK cell culture medium (for example X-VIVOTM medium; Lonza, Basel, Switzerland) or a buffer (such as PBS) and at a temperature sufficient for binding of the anti-CD38 antibody-protein G complex to CD38, for example 4°C to 37°C, such as at room temperature.
- a suitable medium such as an NK cell culture medium (for example X-VIVOTM medium; Lonza, Basel, Switzerland) or a buffer (such as PBS) and at a temperature sufficient for binding of the anti-CD38 antibody-protein G complex
- the anti-CD38 antibody-protein G complex can stably bind to NK cells for a period of time following removal of the antibody-protein G complex from the medium (for example, following washing of the NK cells after contacting with the antibody-protein G complex). Therefore, in some examples, the population of NK cells is contacted with the anti- CD38 antibody-protein G complex at least 2 hours prior to contacting the antibody-protein G complex-bound NK cells with CD38-expressing cells or prior to administering to a subject.
- the population of NK cells can be contacted with the anti-CD38 antibody-protein G complex for at least about 30 minutes to 3 weeks (for example, about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 14 days, or about 21 days) prior to administration to a subject or contacting with CD38-expressing cells.
- the NK cells that are contacted with the anti-CD38 antibody-protein are contacted with the anti-CD38 antibody-protein
- NK cells for example, NK cells from a blood sample from the same subject that is to be treated using the methods described herein.
- the NK cells are allogeneic, for example, from a different individual that the subject that is to be treated. Allogeneic NK cells may be from a related or unrelated donor and may be either partially or fully HLA- matched.
- the population of NK cells (for example a population of NK cells from a subject) is collected and used fresh or is collected and cultured for 12-36 hours in growth media or cytokines (such as IL-15 and/or IL-2 or other cytokines) prior to contacting with an anti-CD38 antibody-protein G complex.
- cytokines such as IL-15 and/or IL-2 or other cytokines
- they are expanded ex vivo prior to contacting with an anti-CD38-protein G complex.
- NK cells (such as CD37CD56 "1" cells) are expanded by culturing the cells in a suitable cell culture medium (such as X-VIVOTM medium) in the presence of one or more cytokines (for example IL-2) for about 1 to 30 days.
- NK cells can also be done in the presence of feeder cells, such as EBV-LCL cells, K562-mbl5-41BBL cells, K562 cells genetically modified to express other molecules to expand NK cells such as membrane bound IL-21, NK-depleted PBMCs, stromal cells, or irradiated tumor cells (such as HFWT).
- feeder cells such as EBV-LCL cells, K562-mbl5-41BBL cells, K562 cells genetically modified to express other molecules to expand NK cells such as membrane bound IL-21, NK-depleted PBMCs, stromal cells, or irradiated tumor cells (such as HFWT).
- NK cells can also be expanded with cytokines alone without feeder cells in media containing other NK cell growth factors such as nicotinamide. Any feeder cell population used to expand NK cells are first gamma-irradiated prior to their use. Methods of expanding NK cells are known to one skilled in the art (see,
- a disorder such as a hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hematoma, hem
- hyperproliferative disorder or an autoimmune disorder that include administering to a subject with the disorder a population of NK cells that are bound to an anti-CD38 antibody-protein G complex and administering to the subject an anti-CD38 antibody or a fragment thereof.
- the methods include treating or inhibiting a hyperproliferative disorder, such as a hematological malignancy or a solid tumor.
- hematological malignancies include leukemias, including acute leukemias (such as l lq23-positive acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), T-cell large granular lymphocyte leukemia, polycythemia vera, lymphoma, diffuse large B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma (indolent and high grade forms), man
- solid tumors such as sarcomas and carcinomas
- solid tumors include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer (including basal breast carcinoma, ductal carcinoma and lobular breast carcinoma), lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hep
- hematological malignancies that can be inhibited or treated by the methods disclosed herein include but are not limited to multiple myeloma, chronic lymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, pro- lymphocytic/myelocytic leukemia, plasma cell leukemia, NK cell leukemia, Waldenstrom macro globulinemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma.
- solid tumors that can be treated or inhibited by the methods disclosed herein include lung carcinoma, prostate cancer, pancreatic cancer (for example, insulinoma), breast cancer, colorectal adenocarcinoma or squamous cell carcinoma, neuroblastoma, testicular cancer (such as seminoma), and ovarian cancer.
- the cells of the hematological malignancy or the solid tumor express or overexpress CD38.
- the subject has multiple myeloma.
- the methods disclosed herein may be used to treat autoimmune disorders (such as systemic lupus, rheumatoid arthritis, multiple sclerosis, erythematosus, or asthma).
- autoimmune disorders such as systemic lupus, rheumatoid arthritis, multiple sclerosis, erythematosus, or asthma.
- the cells that cause or contribute to the autoimmune disorder express CD38.
- the methods disclosed herein may be used to treat any disorder associated with the production of an antibody that leads to disease.
- anti-phospholipid antibody syndrome for example anti-phospholipid antibody syndrome, lupus, acquired factor VIII inhibitor, antibody mediated pure red cell aplasia, HLA allo- immunization or any disease caused by HLA antibodies such as platelet transfusion refractoriness, to eradicate undesirable antibody populations such as HLA antibodies prior to solid organ or bone marrow or peripheral blood or cord blood transplantation, to eradicate RBC or platelet
- the methods disclosed herein include treating a hyperproliferative disorder or an autoimmune disorder in a subject by administering to the subject both an anti-CD38 antibody and a population of NK cells bound to an anti-CD38 antibody-protein G complex.
- the subject is administered an effective dose of anti-CD38 antibody (such as
- the subject is administered about 0.1 mg/kg to about 100 mg/kg of the anti-CD38 antibody (such as about 0.5-10 mg/kg, about 1-20 mg/kg, about 10-50 mg/kg, about 20-100 mg/kg, for example, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 8 mg/kg, about 10 mg/kg, about 16 mg/kg, about 20 mg/kg, about 24 mg/kg, about 36 mg/kg, about 48 mg/kg, about 60 mg/kg, about 75 mg/kg, or about 100 mg/kg).
- An effective amount of the anti-CD38 antibody can be selected by a skilled clinician, taking into consideration the disorder, the general condition of the subject, any additional treatments the subject is receiving or has previously received, and other relevant factors.
- the subject is also administered a population of NK cells that are bound to the anti-CD38 antibody-protein G complex, for example about 10 4 to 10 11 NK cells (such as about 10 5 , about 10 6 , about 10 7 , about 10 8 , about 10 9 , about 10 10 , or more NK cells).
- about 10 6 to 10 9 NK cells/kg are administered to a subject.
- Both the anti-CD38 antibody and the population of NK cells bound to the anti-CD38 antibody- protein G complex are typically administered parenterally, for example intravenously.
- the anti-CD38 antibody and/or the population of NK cells bound to the anti-CD38 antibody-protein G are administered locally, for example by injection or infusion to a tumor or close to a tumor.
- One of skill in the art can determine appropriate routes of administration.
- the population of NK cells bound to the first anti-CD38 antibody-protein G complex and/or the second anti-CD38 antibody can be administered.
- the population of NK cells bound to first anti-CD38 antibody-protein G complex can be administered every other day, twice per week, weekly, every other week, every three weeks, monthly, or less frequently.
- the second anti-CD38 antibody can be administered every other day, twice per week, weekly, every other week, every three weeks, monthly, or less frequently.
- the population of NK cells bound to the first anti-CD38 antibody -protein G complex and the second anti-CD38 antibody are administered on the same schedule or on a staggered schedule.
- a specific example of an administration schedule is provided below; however, a skilled clinician can select alternative schedules based on the subject, the condition being treated, the previous treatment history, and other factors.
- the population of NK cells that are bound to the first anti-CD38 antibody-protein G complex is administered to the subject before, after, or substantially simultaneously with the second anti-CD38 antibody.
- the population of NK cells bound to the first anti- CD38 antibody-protein G complex is administered after the second anti-CD38 antibody, for example within about 1 hour to three weeks (such as within about 1-48 hours, about 2-24 hours, about 12-72 hours, about 1-5 days, about 7-21 days, about 10-14 days, for example, within about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 14 days, or about 21 days) of the administration of the second anti-CD38 antibody.
- the population of NK cells bound to the first anti-CD38 antibody-protein G complex is administered to the subject within about 24 hours of the administration of the second anti-CD38 antibody. In some examples, this administration pattern is repeated two times per week for at least two weeks or once weekly for at least two weeks.
- the subject (such as a subject with a hyperproliferative disorder) is also administered one or more additional treatments, such as one or more chemo therapeutic agents and/or radiation therapy.
- the subject is treated as described herein, and is also administered an immunomodulatory agent (such as lenalidomide, thalidomide, or pomalidomide), a proteasome inhibitor (such as bortezomib, carfilzomib, salinosporamide A, epoxomicin, marizomib (NPI-0052), ixazomib (MLN9708), CEP18770, or oprozomib (ONX0912)), steroids (such as dexamethasone, prednisone, prednisolone, or methylprednisolone), and/or other chemo therapeutics (such as melphalan).
- an immunomodulatory agent such as lenalidomide, thalidomide, or pomalidomide
- the subject may be administered a combination therapy with the anti-CD38 antibody, such as daratumumab (or another anti-CD38 antibody) in combination with lenalidomide, alone, or in combination with bortezomib.
- the subject may be administered daratumumab (or another anti-CD38 antibody), lenalidomide, bortezomib, and dexamethasone, or daratumumab (or another anti-CD38 antibody), melphalan, prednisone, and bortezomib.
- chemotherapeutic agents for administration to a subject in combination with the anti-CD38 antibody.
- agents include alkylating agents, such as nitrogen mustards (such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard or chlorambucil), alkyl sulfonates (such as busulfan), nitrosoureas (such as carmustine, lomustine, semustine, streptozocin, or dacarbazine); antimetabolites such as folic acid analogs (such as methotrexate), pyrimidine analogs (such as 5-FU or cytarabine), and purine analogs, such as mercaptopurine or thioguanine; or natural products, for example vinca alkaloids (such as vinblastine, vincristine, or vindesine), epipodophyllotoxins (such as etoposide or teniposide), antibiotics (such as dactinomycin
- Additional agents include platinum coordination complexes (such as cis-diamine-dichloroplatinum II, also known as cisplatin), substituted ureas (such as hydroxyurea), methyl hydrazine derivatives (such as procarbazine), and adrenocrotical suppressants (such as mitotane and aminoglutethimide); hormones and antagonists, such as adrenocorticosteroids (such as prednisone), progestins (such as hydroxyprogesterone caproate, medroxyprogesterone acetate, and magestrol acetate), estrogens (such as diethylstilbestrol and ethinyl estradiol), antiestrogens (such as tamoxifen), and androgens (such as testosterone proprionate and fluoxymesterone).
- platinum coordination complexes such as cis-diamine-dichloroplatinum II, also known as cisplatin
- Examples of the most commonly used chemotherapy drugs include adriamycin, melphalan (Alkeran®) Ara-C (cytarabine), carmustine, busulfan, lomustine, carboplatinum, cisplatinum, cyclophosphamide (Cytoxan®), daunorubicin, dacarbazine, 5- fluorouracil, fludarabine, hydroxyurea, idarubicin, ifosfamide, methotrexate, mithramycin, mitomycin, mitoxantrone, nitrogen mustard, paclitaxel (or other taxanes, such as docetaxel), vinblastine, vincristine, VP- 16, while newer drugs include gemcitabine (Gemzar®), trastuzumab (Herceptin®), irinotecan (CPT-11), leustatin, navelbine, rituximab (Rituxan®) imatinib (STI-571),
- the subject is administered one or more cytokines (such as IL-2, IL- 15, IL-21, and/or IL-12) after NK cell infusion to support survival and/or growth of NK cells.
- administration of the NK cells bound to a first anti-CD38 antibody- protein G complex and a second anti-CD38 antibody to a subject decreases the volume or number of cells of a hematological malignancy (such as MM), a tumor, and/or a metastatic tumor.
- the disclosed methods can result in a decrease in the symptoms associated with a hyperproliferative disorder, an increase in survival (including overall survival, progression-free survival and/or metastasis-free survival), or partial or complete remission of disease.
- Example 1 The present disclosure is illustrated by the following non-limiting Examples.
- Example 1 The present disclosure is illustrated by the following non-limiting Examples.
- This example describes the effect of daratumumab on NK cells and the role of CD 16 in the toxicity of daratumumab to NK cells.
- CD38 is expressed on T cells, B cells, NK cells, and myeloma cells (FIG. 1).
- NK cells were isolated from PBMC using CD3 depletion followed by CD56 selection and were stained with an anti-CD38 antibody or cultured for 18 hours in IL-2 containing media (500 IU/ml) or were expanded ex vivo for 7-14 days in IL-2 containing media (500 IU/ml) using irradiated EBV-LCL feeder cells. The NK cells were then stained with an anti-CD38 antibody.
- NK cells were then stained with an anti-CD38 antibody.
- expression of CD38 increased compared to CD38 expression on resting NK cells, (FIG. 2A and 2B).
- NK cells which had been expanded as above for 14 days were cultured in media containing daratumumab at a dose of 1 ⁇ g/ml (FIG. 3B) or 10 ⁇ g/ml (FIG. 3C) for 4 hours, cell viability assessed by staining NK cells with annexin V and 7AAD was decreased compared to control expanded NK cells which were cultured in media without daratumumab (FIGS. 3A-C).
- NK cells were 87% viable in the control population (FIG. 3A), but only 68% and 70% viable when cultured with 1 ⁇ g/ml or 10 ⁇ g/ml of daratumumab, respectively (FIGS. 3B and 3C).
- NK cells enriched from PBMC were expanded using EBV-LCL for 14 days as previously described then were sorted using flow cytometry into CD16 + or CD 16 " cell populations and CD38 expression was analyzed 48 hours after sorting. CD38 expression was similar on both CD16 + and CD 16 " NK cells (FIGS. 4A and 4B).
- the addition of daratumumab to the media for 4 hours at a concentration of either 10 ⁇ g/ml or 100 ⁇ g/ml did not have any effect on viability of CD 16 " NK cells as assessed by staining for annexin V (FIG. 5 A), but did decrease viability of CD16 + NK cells (FIG. 5B). This suggests that CD16 likely mediates NK cell killing by daratumumab through ADCC.
- Example 2 Example 2
- This example describes the effect of daratumumab on NK cell killing of tumor cells.
- NK cells were expanded for 14 days as described in Example 1 using irradiated EBV-LCL feeder cells.
- Tumor targets including K562 cells (myelogenous leukemia which is CD38 negative), MM1S cells (multiple myeloma, which is CD38 positive), or OPM1 cells (multiple myeloma, which are CD38 positive) were labeled with 51 Cr then were co-cultured for 5 hours with expanded NK cells in control media without daratumumab or with NK cells in media containing 1 or 10 ⁇ g/ml of daratumumab.
- NK cell effector to tumor target ratios varied between 1: 1, 5: 1, and 10: 1. Adding daratumumab to a co- culture of tumor cells and NK cells had no effect on the lysis of MM IS or OPM 1 cells (FIG. 6B- 6C) and actually resulted in a small decrease in K562 cells at the 5: 1 E:T ratio (FIG. 6A).
- This example describes the effect of high or low affinity CD 16 genotype on killing of NK cells by daratumumab.
- NK cells with the 158V genotype have higher affinity for IgGl and IgG3 than those with the 158F genotype and exert ADCC more efficiently.
- DNA was extracted from cryopreserved PBMC from 10 healthy donors and CD 16 genotypes were determined using TaqMan® allelic discrimination.
- NK cells from four donors were expanded for 14 days using irradiated EBV-LCL feeder cells as previously described. Two donors had high affinity IgG binding genotype (NK D96 and D09) and two had low affinity IgG binding genotype (NK D64 and D136).
- NK cells Day 14 expanded NK cells were cultured in parallel for 2 hours in media with or without daratumumab at a concentration of 10 ⁇ g/ml.
- NK cells from donors with low or high affinity CD16 had similar levels of CD38 expression as assessed by FACS (left panels of FIGS. 8A-8B and 9A-9B).
- the right panels of FIGS. 8A-8B and 9A-9B show CD38 staining on NK cells from donors when NK cells were treated with daratumumab at 10 g/ml for 2 hours, showing the CD38 epitopes were completely bound by the intact daratumumab antibody.
- NK cells with low affinity CD 16 were less susceptible to daratumumab-induced cell death in the presence of 10 ⁇ g/ml daratumumab than NK cells with high affinity CD 16 (Table 1 ) .
- NK cells from one donor with high affinity IgG binding genotype were flow sorted into CD16 + and CD 16 " populations then were cultured for 2 hours in media with
- daratumumab at a concentration of 10 ⁇ g/ml were assessed for cell death by staining with annexin V.
- NK cell killing by daratumumab was shown to be mediated via CD 16, as CD 16 " NK cells were not killed by daratumumab (FIG. 10A) in contrast to CD16 + NK cells, where substantial NK cell death was observed (FIG. 10B).
- FIGS. 11A and 1 IB are graphs showing U226 myeloma cell lysis by low affinity CD 16 NK cells (FIG.
- FIG. 11 A or high affinity CD16 NK cells (FIG. 1 IB) when tumor cells are cultured with daratumumab alone (left), NK cells alone (center), or NK cells and daratumumab (right).
- Both low and high affinity CD 16 NK cells killed U226 myeloma target cells, and this killing was enhanced by daratumumab.
- the high affinity CD 16 NK cells showed a greater increase in U226 cell killing than low affinity NK cells (7-fold vs. 5-fold; FIG. 12).
- This example describes the effect of blocking CD38 on NK cells with protein G bound daratumumab on NK cell toxicity of daratumumab.
- Daratumumab (100 ⁇ g) was incubated with protein G (50 ⁇ g) in 100 ⁇ of phosphate- buffered saline (PBS) for five minutes at room temperature. A fraction of this mixture (2 ⁇ g daratumumab) was added to 2 million human NK cells from donors with either low (donor NK0136) or high (donor NK1096) CD16 then resuspended in 100 ⁇ PBS and incubated for 30 minutes at room temperature. Some cells were incubated with equivalent amounts of protein G alone without daratumumab or were left untreated. The NK cells were then washed in 15 ml of
- NK cells PBS twice and resuspended in NK medium and cultured for 24 hours with or without daratumumab (2 ⁇ g/ml).
- the NK cells were stained with annexin V, anti-CD38, anti-CD16, anti-CD56 and analyzed by flow cytometry.
- FIGS. 16A and 16B are schematics showing a proposed mechanism for protection of NK cells from daratumumab- mediated apoptosis while maintaining or even augmenting apoptosis of CD38-expressing tumor cells.
- This example describes the effect of daratumumab on IFNy secretion level in NK cells.
- Expanded NK cells from two donors were flow sorted into CD16 + and CD 16 " populations, then were cultured for 2 hours in media with daratumumab at a
- FIGS. 17A and 17B show a 2-3-fold increase in IFNy secretion in CD16 + NK cells vs. untreated cells after treatment with daratumumab in both donors. No effect of daratumumab treatment on IFNy secretion levels was observed in CD16 " NK cells. Expanded NK cells from these two donors were also pre-incubated with protein G alone or with protein G-bound daratumumab for 30 minutes. Control cells were left untreated.
- FIGS. 18A and 18B show an increase in IFNy secretion by NK cells treated by daratumumab vs. control untreated cells or cells treated with protein G alone. Pretreatment of NK cells with protein G-bound daratumumab inhibited this increase in IFNy secretion level.
- NK1096 and NK0136 were pre-incubated for 30 minutes with protein G-bound daratumumab, protein G alone, or were left untreated. The cells were then co-cultured for 24 hours with or without K562 and Raji cancer cell lines. No daratumumab was added to the cell culture.
- FIGS. 19A and 19B show that treatment of NK cells with protein G-bound daratumumab did not impair the capacity of NK cells to release IFNy in response to tumor cells.
- This example describes methods for testing the efficacy of treating a tumor with
- daratumumab-protein G complex-treated NK cells in an animal tumor model system can also be used to successfully treat a tumor in an animal model.
- Immuno-deficient mice are injected in the tail vein with 1 million luciferase transduced MM1S myeloma tumor cells which are CD38 + . Tumor cells home to the bone marrow within 72 hours and can be repeatedly imaged using bioluminescent imaging (BLI) to quantitate tumor bulk. Tumors are allowed to become established for 1 week, then mice are divided into the following cohorts. Cohort 1 receives saline alone i.p. Cohort 2 receives a single i.p. injection of daratumumab at a dose of 20 ⁇ g. Cohort 3 receives 5 million human NK cells i.v. which have been expanded in vitro for 14 days using EBV-LCL feeder cells as previously described.
- BBI bioluminescent imaging
- Cohort 4 receives 5 million human NK cells i.v. which have been expanded in vitro for 14 days using EBV-LCL feeder cells as previously described which are treated with daratumumab- protein G complex (5 ⁇ g/ml in PBS) for 20 minutes at room temperature then washed and infused into mice.
- Cohort 5 receives a single i.p. injection of daratumumab at a dose of 20 ⁇ g followed 2 hours later by a single injection of 5 million human NK cells which have been expanded in vitro for 14 days using EBV-LCL feeder cells as previously described.
- Cohort 6 receives a single i.p.
- mice All mice cohorts are weighed twice weekly and undergo twice weekly BLI imaging to quantitate the bulk of their tumors and are followed for survival.
- This example describes exemplary methods for adoptive transfer of daratumumab-protein G-treated NK cells, for example for treatment of multiple myeloma.
- methods that deviate from these specific methods can also be used to successfully for adoptive transfer and treatment of multiple myeloma or other malignancies.
- Subjects with multiple myeloma are identified, for example, using standard diagnostic criteria. In some examples, some subjects may be treated with daratumumab alone or in
- NK cells are obtained either from the subject or a donor.
- the NK cells are expanded ex vivo using irradiated EBV-LCL feeder cells as previously described. Following a 14- 21 day ex vivo expansion, 10 8 NK cells/kg are treated with 1-20 ⁇ g/ml daratumumab-protein G for 10-60 minutes at room temperature. The NK cells are then washed to remove unbound antibody- protein G and are resuspended at a concentration of 50 million NK cells/ml in PBS containing either autologous plasma (1-10%) or human serum albumin.
- Daratumumab (2-24 mg/kg) is administered intravenously to the subject with multiple myeloma.
- 10 8 NK cells/kg from the preparation of NK cells bound to the daratumumab-protein G complex is administered intravenously to the subject.
- Treatment with daratumumab followed within 24 hours with NK cells bound to the daratumumab-protein G complex is repeated weekly for at least 3 weeks.
- subjects are monitored for reductions in one or more clinical symptoms associated with multiple myeloma.
- subjects are analyzed one or more times, starting 7 days following treatment.
- Subjects can be monitored using any method known in the art. For example, serum or urine M protein levels or kappa or lambda free light chains of the subject can be assessed. Other signs and symptoms of multiple myeloma can also be assessed, such as blood calcium levels, bone marrow plasma cell percentage, or presence or size of bone lesions or plasmacytomas.
- a reduction in one or more clinical symptoms associated with multiple myeloma indicates the effectiveness of the treatment.
- NK cells bound to daratumumab-protein G complex can be tested for safety in animals, and then used for clinical trials in animals or humans.
- animal models of cancer are employed to determine therapeutic value and/or dosages of the disclosed agents.
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Abstract
La présente invention concerne des procédés d'inhibition de la croissance ou la prolifération de cellules exprimant CD38 par la mise en contact des cellules exprimant CD38 avec 1) des cellules NK liées à un complexe anticorps anti-CD38-protéine G et 2) un anticorps anti-CD38, dans un ordre quelconque ou simultanément. L'invention concerne également des procédés de traitement ou d'inhibition d'un trouble hyperprolifératif ou d'un trouble auto-immun chez un sujet par l'administration au sujet 1) de cellules NK liées à un complexe anticorps anti-CD38-protéine G et 2) d'un anticorps anti-CD38, dans un ordre quelconque ou simultanément.
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US20180325951A1 (en) * | 2014-11-14 | 2018-11-15 | The Usa, As Represented By The Secretary, Department Of Health And Human Services | Nk cells with an increased antibody-dependent cellular toxicity (adcc) against tumors |
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