WO2020206026A1 - Anti-ccr5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by dna damaging chemotherapy - Google Patents
Anti-ccr5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by dna damaging chemotherapy Download PDFInfo
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
Definitions
- CCR5 plays an important role in tumor invasion and metastasis. Increased CCR5 expression is an indicator of disease status in several cancers. And published studies have shown that blocking CCR5 can reduce tumor metastases in laboratory and animal models of aggressive breast and prostate cancer.
- CCR5 signaling has anti-tumor effects, acting as a co-stimulatory molecule for T cell activation and increasing T cell chemotaxis to the tumor microenvironment. See Gao et al., CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells , OPEN BIOL.,
- CCL5/CCR5 axis signaling may be preferentially activated in certain types of cancers, for example breast and prostate cancers, and that such signaling facilitates disease progression.
- cancer cells can overexpress CCL5, CCR5, or both, likely contributing to their growth and proliferation via the effects of CCR5 signaling on mechanistic target of rapamycin (mTOR).
- CCR5 extracellular or cell transmembrane CCR5 binding agents
- PRO 140 extracellular
- maraviroc transmembrane
- other compounds such as vicriviroc, aplaviroc, SCH-C, and TAK-779
- PA14, 2D7, RoAbl3, RoAbl4, 45523, etc. It has been found that the most potently antiviral anti-CCR5 monoclonal antibodies including, for example, PRO 140, bind CCR5 receptor amino acid residues in EL2 alone or in combination with Nt residues.
- CCR5 receptor binding sites for anti- CCR5 monoclonal antibodies are distinct from those of small-molecule CCR5 antagonists. That is, available small-molecule CCR5 antagonists, such as maraviroc, bind the hydrophobic cavity formed by the transmembrane helices, i.e., not the extracellular Nt or loop regions.
- the amino acid residue E283 in the seventh transmembrane region has been specifically identified as a principle site or interaction for small molecules, and maraviroc and vicriviroc have been found to bind to identical sets of CCR5 receptor amino acids. Olson et al., CCR5 Monoclonal Antibodies for HIV- 1 Therapy , CURR. OPIN.
- CCL5 expression associated with immune cell activation can be exploited by cancer cells in the tumor microenvironment, and blocking CCR5 signaling using inhibitors such as maraviroc may have anti-tumor effects.
- CD4 + and CD8 + T cells at the invasive margin expressed CCL5 which was associated with T cell exhaustion, tumor proliferation, invasive tumor cell behavior, and increased production of matrix metalloproteinases by tumor-associated macrophages.
- Halama et ah Tumoral Immune Cell Exploitation in Colorectal Cancer Me tastases Can Be Targeted Effectively by Anti- CCR5 Therapy in Cancer Patients, CANCER CELL, 29: 587-601 (2016).
- Inhibiting CCL5 with maraviroc led to repolarization of tumor-associated macrophages and tumor cell death. Halama et al. (2016).
- CCL5/CCR5 axis as a therapeutic target will need to accommodate two opposing demands: the need to inhibit the detrimental involvement of CCL5 and CCR5 in specific malignant diseases while protecting their potentially beneficial activities in immunity.
- TNBC Triple Negative Breast Cancer
- ER estrogen receptor
- PgR progesterone receptor
- HER-2 human epidermal growth factor receptor-2
- Chemotherapy is still the main treatment option for TNBC patients, and standard treatment is surgery with adjuvant chemotherapy and radiotherapy.
- TNBC responds to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis still remains poor.
- neoadjuvant chemotherapy is frequently used for triple-negative breast cancers [Hudis 2011] This allows for a higher rate of breast-conserving surgeries and, from evaluating the response to the chemotherapy, gives important clues about the individual responsiveness of the particular cancer to chemotherapy.
- TNBC metastatic TNBC is a complex disease with an unmet need and an unproven treatment regimen in clinics.
- the present disclosure relates to the use of DNA damaging agents and leronlimab (PRO 140), or other anti-CCR5 agents, to treat or prevent cancer metastases and enhance the cell killing ability of the DNA damaging agents by selectively targeting the CCR5 receptor.
- the present disclosure relates to the use of DNA damaging agents and leronlimab (PRO 140), or other anti-CCR5 agents, to treat or prevent cancer metastases and reduce circulating tumor cells (CTC) or putative metastatic tumor cells in the peripheral blood following treatment, .reduce CCR5 expression on cancer-associated cells after following treatment, decrease volume in tumor size following treatment.
- CTC circulating tumor cells
- the present disclosure may be used to treat or prevent subjects with cancer and, particularly, subjects with metastatic CCR5+ cancer.
- leronlimab can effectively block CCR5 positive breast cancer metastasis. Also provided are murine xenograft models that show that, by reducing the ability of breast cancer cells to metastasize, tumors are more contained. Additionally, it is shown that leronlimab can potentially provide standard DNA damaging chemotherapies more time to work, potentially providing significantly improved efficacy of existing cancer therapies with fewer side effects. That is, leronlimab enhances the effect of DNA damaging agents to kill cancer cells.
- FIGS 1 A and IB Leronlimab binds CCR5 in human breast cancer cells.
- PRO140 blocks human CCR5-mediated signaling in human breast cancer cells.
- FIGS 3A-3D Leronlimab blocks CCR5-mediated invasion of human breast cancer cells into extracellular matrix.
- FIGS 4A and 4B Leronlimab block breast cancer metastasis in mice.
- FIGS 5A and 5B Leronlimab enhances the cell death induced by Doxorubicin, a DNA damage inducing chemotherapy agent.
- Figures 6A-6C show immunohistochemical staining for CCR5 in tissue samples from a subject with triple negative breast cancer.
- Figure 6A shows representative images of IHC for CCR5.
- Immunohistochemistry analysis on archival tissue showed high predominance of CCR5+ tumor infiltrating leukocytes.
- Increased CCR5 expression is an indicator of disease status in several cancers including, but not limited to, breast cancer.
- leronlimab leronlimab
- the present disclosure relates to the use of leronlimab (PRO 140), or other anti-CCR5 agents, to treat, reduce, prevent, or block cancer metastases and/or enhance the cell killing ability of DNA damaging
- chemokine receptors and its ligands also referred as chemoattractant or chemotactic cytokines, are involved in the process of cancer cells tropism by specific organs [Moser, 2001][Neagu,
- C-C Chemokine receptor type-5 (CCR5) is selectively reexpressed on the surface of tumor cells during the dedifferentiation and transformation process (velasco-velazquez-2012). Velasco-Velazquez et al.
- CCR5 has been shown to be sufficient to induce in vitro invasiveness and metastasis of breast cancer cells that is blocked by CCR5 inhibitors [Velasco- Velazquez, 2012]
- CCR5 inhibitors such as Maraviroc, effectively blocked lung metastases in breast cancer tumor model.
- CCR5 binding agents including leronlimab (PRO 140) show a significant reduction in tumor volume in a breast cancer tumor model.
- Another cancer hallmark that CCR5 presents a potential role is the DNA repair pathways. This cancer characteristic attenuates apoptosis and contributes to chemotherapy resistance and tumor cells immortality. Studies have correlated the altered expression of C-C
- Chemokine Ligand type-5 (CCL5) with disease progression in patients with breast cancer [Luboshits, 1999] [Niwa, 2001] [Zhang, 2009]
- CCR5 binding agents such as antagonists Maraviroc and Vicriviroc, dramatically enhanced cell killing mediated by DNA-damaging chemotherapeutic agents.
- Single-cell analysis revealed CCR5 governs PI3K/Akt, ribosomal biogenesis, and cell survival signaling [Jiao-2018]
- the role of CCR5 blockade of the CCL5-CCR5 pathway in immune control of tumors has recently been shown and provided new horizon to target this deadly disease [de Oliveira, 2017, Del Prete, 2017, Lanitis, 2017]
- CCR5 binding agents such as antagonists Maraviroc and Vicriviroc
- Targeted therapy with one or more CCR5 binding agents may have a potential to increase overall response rate due to a synergy in DNA crosslink strand break of chemotherapeutic agents, such as carboplatin, and reduce DNA repair secondary to CCR5 binding by Leronlimab (PRO 140).
- chemotherapeutic agents such as carboplatin
- any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
- any number range recited herein relating to any physical feature, such as dose are to be understood to include any integer within the recited range, unless otherwise indicated.
- the term "about” means ⁇ 20% of the indicated range, value, or structure, unless otherwise indicated.
- a protein domain, region, or module e.g., a binding domain, hinge region, linker module
- a protein which may have one or more domains, regions, or modules
- chemokine means a cytokine that can stimulate leukocyte movement.
- Chemokines may be characterized as either cys-cys or cys-X-cys depending on whether the two amino terminal cysteine residues are immediately adjacent or separated by one amino acid. It includes, but is not limited to, CCL5 (also known as RANTES), MPMa, MIR-Ib, or SDF-1, or another chemokine which has similar activity.
- chemokine receptor means a member of a homologous family of seven-transmembrane spanning cell surface proteins that bind chemokines.
- CCR5 is a chemokine receptor which binds members of the C— C group of chemokines and whose amino acid sequence comprises that provided in Genbank Accession Number 1705896, and related polymorphic variants.
- antibody means an immunoglobulin molecule comprising two heavy chains and two light chains and that recognizes an antigen.
- the immunoglobulin molecule may derive from any of the commonly known classes or isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM.
- IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3, and IgG4. It includes, by way of example, both naturally occurring and non-naturally occurring antibodies.
- antibody includes polyclonal and monoclonal antibodies, and monovalent and divalent fragments thereof.
- antibody includes chimeric antibodies, wholly synthetic antibodies, single chain antibodies, and fragments thereof.
- an antibody can be labeled with a detectable marker. Detectable markers include, for example, radioactive or fluorescent markers.
- the antibody may be a human or nonhuman antibody.
- the nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in humans. Methods for humanizing antibodies are known to those skilled in the art.
- monoclonal antibody also designated as “mAb” is used to describe antibody molecules whose primary sequences are essentially identical and which exhibit the same antigenic specificity.
- Monoclonal antibodies may be produced by hybridoma, recombinant, transgenic, or other techniques known to one skilled in the art.
- variable domain VH
- CHI variable domain
- CH2, CH3, and CH4 constant domains
- light chain means the smaller polypeptide of an antibody molecule composed of one variable domain (VL) and one constant domain (CL), or fragments thereof.
- a "binding fragment” or an "antigen-binding fragment or portion” of an antibody refers to the fragment or portion of an intact antibody that has or retains the ability to bind to the antigen target molecule recognized by the intact antibody, including fragment antigen binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments.
- Fab fragment antigen binding
- F(ab')2 fragments fragment antigen binding
- Fab' fragments fragment antigen binding
- Fv fragments fragment antigen binding
- rlgG recombinant IgG fragments
- single chain antibody fragments including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody)
- immunoglobulins such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific, antibodies, diabodies, triabodies, tetrabodies, tandem di-scFv, and tandem tri-scFv.
- Fab means a monovalent antigen binding fragment of an immunoglobulin that consists of one light chain and part of a heavy chain. It can be obtained by brief papain digestion or by recombinant methods.
- F(ab')2 fragment means a bivalent antigen binding fragment of an immunoglobulin that consists of both light chains and part of both heavy chains. It can be obtained by brief pepsin digestion or recombinant methods.
- CDR or “complementarity determining region” means a highly variable sequence of amino acids in the variable domain of an antibody.
- humanized describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules. In one embodiment of the humanized forms of the antibodies, some, most, or all of the amino acids outside the CDR regions have been replaced with amino acids from human immunoglobulin molecules but where some, most, or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions, or modifications of amino acids are permissible as long as they would not abrogate the ability of the antibody to bind a given antigen. Suitable human immunoglobulin molecules would include IgGl, IgG2, IgG3, IgG4, IgA, and IgM molecules. A "humanized” antibody would retain a similar antigenic specificity as the original antibody, e.g., in the present disclosure, the ability to bind CCR5.
- site directed mutagenesis is used to graft the CDRs onto the framework.
- U.S. Pat. Nos. 5,585,089 and 5,693,761 and WO 90/07861 also propose four possible criteria which may be used in designing the humanized antibodies.
- the first proposal was that for an acceptor, use a framework from a particular human immunoglobulin that is unusually homologous to the donor immunoglobulin to be humanized, or use a consensus framework from many human antibodies.
- the second proposal was that if an amino acid in the framework of the human immunoglobulin is unusual and the donor amino acid at that position is typical for human sequences, then the donor amino acid rather than the acceptor may be selected.
- the third proposal was that in the positions immediately adjacent to the 3 CDRs in the humanized immunoglobulin chain, the donor amino acid rather than the acceptor amino acid may be selected.
- the fourth proposal was to use the donor amino acid residue at the framework positions at which the amino acid is predicted to have a side chain atom within 3 A of the CDRs in a three dimensional model of the antibody and is predicted to be capable of interacting with the CDRs.
- the above methods are merely illustrative of some of the methods that one skilled in the art could employ to make humanized antibodies.
- the affinity and/or specificity of the binding of the humanized antibody may be increased using methods of directed evolution as described in Wu et ah, J. MOL. BIOL., 284: 151 (1999) and U.S. Pat. Nos. 6,165,793; 6,365,408; and 6,413,774.
- variable regions of the humanized antibody may be linked to at least a portion of an immunoglobulin constant region of a human immunoglobulin.
- the humanized antibody contains both light chain and heavy chain constant regions.
- the heavy chain constant region usually includes CHI, hinge, CH2, CH3, and, sometimes, CH4 region.
- the constant regions of the humanized antibody are of the human IgG4 isotype.
- the antibodies, or binding fragments, disclosed herein may either be labeled or unlabeled.
- Unlabeled antibodies can be used in combination with other labeled antibodies (second antibodies) that are reactive with a humanized antibody, such as antibodies specific for human immunoglobulin constant regions.
- second antibodies labeled antibodies
- the antibodies can be directly labeled.
- labels can be employed, such as radionuclides, fluors, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, ligands (particularly haptens), etc.
- Numerous types of immunoassays are available and are well known to those skilled in the art for detection of CCR5- expressing cells or detection of CCR5 modulation on cells capable of expressing CCR5.
- the present disclosure also provides antibody or antibody fragment- polymer conjugates having an effective size or molecular weight, or incorporate other half-life extension technologies, that confer an increase in serum half-life, an increase in mean residence time in circulation (MRT), and/or a decrease in serum clearance rate over underivatized antibody fragments.
- Antibody fragment-polymer conjugates can be made by derivatizing the desired antibody fragment with an inert polymer. It will be appreciated that any inert polymer which provides the conjugate with the desired apparent size or which has the selected actual molecular weight is suitable for use in constructing antibody fragment-polymer conjugates of the disclosure. Many inert polymers are suitable for use in pharmaceuticals.
- nonproteinaceous polymer ordinarily is a hydrophilic synthetic polymer, i.e., a polymer not otherwise found in nature.
- hydrophilic polyvinyl polymers fall within the scope of this disclosure, e.g., polyvinyl alcohol and polyvinylpyrrolidone.
- polyalkylene ethers such as polyethylene glycol (PEG); polyoxyalklyenes such as polyoxyethylene, polyoxypropylene, and block copolymers of polyoxyethylene and polyoxypropylene (Pluronics); polymethacrylates; carbomers; branched or unbranched polysaccharides which comprise the saccharide monomers D-mannose, D- and L- galactose, fucose, fructose, D-xylose, L-arabinose, D-glucuronic acid, sialic acid, D- galacturonic acid, D-mannuronic acid (e.g., polymannuronic acid, or alginic acid), D- glucosamine, D-galactosamine, D-glucose, and neuraminic acid including
- homopolysaccharides and heteropolysaccharides such as lactose, amylopectin, starch, hydroxyethyl starch, amylose, dextran sulfate, dextran, dextrins, glycogen, or the polysaccharide subunit of acid mucopolysaccharides, e.g., hyaluronic acid, polymers of sugar alcohols such as polysorbitol and polymannitol, heparin, or heparon.
- the polymer prior to cross-linking need not be, but preferably is, water soluble but the final conjugate must be water soluble.
- the conjugate exhibits a water solubility of at least about 0.01 mg/ml and more preferably at least about 0.1 mg/ml, and still more preferably at least about 1 mg/ml.
- the polymer should not be highly immunogenic in the conjugate form, nor should it possess viscosity that is incompatible with intraveneous infusion or injection if the conjugate is intended to be administered by such routes.
- the polymer contains only a single group which is reactive. This helps to avoid cross-linking of protein molecules. However it is within the scope of the disclosure to maximize reaction conditions to reduce cross-linking, or to purify the reaction products through gel filtration or ion-exchange chromatography to recover substantially homogeneous derivatives. In other embodiments, the polymer contains two or more reactive groups for the purpose of linking multiple antibody fragments to the polymer backbone.
- Gel filtration or ion-exchange chromatography can be used to recover the desired derivative in substantially homogeneous form.
- the molecular weight of the polymer can range up to about 500,000 D and preferably is at least about 20,000 D, or at least about 30,000 D, or at least about 40,000 D.
- the molecular weight chosen can depend upon the effective size of the conjugate to be achieved, the nature (e.g., structure such as linear or branched) of the polymer and the degree of derivitization, i.e., the number of polymer molecules per antibody fragment, and the polymer attachment site or sites on the antibody fragment.
- the polymer can be covalently linked to the antibody fragment through a multifunctional crosslinking agent which reacts with the polymer and one or more amino acid residues of the antibody fragment to be linked.
- a multifunctional crosslinking agent which reacts with the polymer and one or more amino acid residues of the antibody fragment to be linked.
- directly crosslink the polymer by reacting a derivatized polymer with the antibody fragment, or vice versa.
- the covalent crosslinking site on the antibody fragment includes the N- terminal amino group and epsilon amino groups found on lysine residues, as well other amino, imino, carboxyl, sulfhydryl, hydroxyl, or other hydrophilic groups.
- the polymer may be covalently bonded directly to the antibody fragment without the use of a multifunctional (ordinarily bifunctional) crosslinking agent, as described in U.S. Pat.
- the degree of substitution with such a polymer will vary depending upon the number of reactive sites on the antibody fragment, the molecular weight, hydrophilicity and other characteristics of the polymer, and the particular antibody fragment derivitization sites chosen.
- the conjugate contains from 1 to about 10 polymer molecules, but greater numbers of polymer molecules attached to the antibody fragments of the disclosure are also contemplated.
- the desired amount of derivitization is easily achieved by using an experimental matrix in which the time, temperature, and other reaction conditions are varied to change the degree of substitution, after which the level of polymer substitution of the conjugates is determined by size exclusion chromatography or other means known in the art.
- PEG polymers to modify the antibody fragments of the disclosure are available from Shearwater Polymers, Inc. (Huntsville, Ala.). Such commercially available PEG derivatives include, but are not limited to, amino-PEG, PEG amino acid esters, PEG-hydrazide, PEG-thiol, PEG-succinate, carboxy methylated PEG, PEG-propionic acid, PEG amino acids, PEG succinimidyl succinate, PEG succinimidyl propionate, succinimidyl ester of carboxymethylated PEG, succinimidyl carbonate of PEG, succinimidyl esters of amino acid PEGs, PEG- oxycarbonylimidazole, PEG-nitrophenyl carbonate, PEG tresylate, PEG-glycidyl ether, PEG-aldehyde, PEG- vinyl sulfone, PEG-maleimide, PEG-orthopyridyl-disulfide, heterofunctional
- the reaction conditions for coupling these PEG derivatives will vary depending on the protein, the desired degree of PEGylation, and the PEG derivative utilized. Some factors involved in the choice of PEG derivatives include: the desired point of attachment (such as lysine or cysteine R-groups), hydrolytic stability and reactivity of the derivatives, stability, toxicity and antigenicity of the linkage, suitability for analysis, etc. Specific instructions for the use of any particular derivative are available from the manufacturer.
- the conjugates of may be separated from the unreacted starting materials by gel filtration or ion exchange HPLC.
- anti-chemokine receptor antibody means an antibody which recognizes and binds to an epitope on a chemokine receptor.
- anti-CCR5 antibody means a monoclonal antibody that recognizes and binds to an epitope on the CCR5 chemokine receptor.
- epitope means a portion of a molecule or molecules that forms a surface for binding antibodies or other compounds.
- the epitope may comprise contiguous or noncontiguous amino acids, carbohydrate, or other nonpeptidyl moieties or oligomer-specific surfaces.
- polypeptide means two or more amino acids linked by a peptide bond.
- a “nucleic acid molecule,” or “polynucleotide,” may be in the form of RNA or DNA, which includes cDNA, genomic DNA, and synthetic DNA.
- a nucleic acid molecule may be double stranded or single stranded, and if single stranded, may be the coding strand or non-coding (anti-sense strand).
- a coding molecule may have a coding sequence identical to a coding sequence known in the art or may have a different coding sequence, which, as the result of the redundancy or degeneracy of the genetic code, or by splicing, can encode the same polypeptide.
- “Analogs” of antibodies or binding fragments include molecules differing from the antibodies or binding fragments by conservative amino acid substitutions.
- amino acids may be grouped as follows: Group I (hydrophobic side chains): met, ala, val, leu, ile; Group II (neutral hydrophilic side chains): cys, ser, thr; Group III (acidic side chains): asp, glu; Group IV (basic side chains): asn, gin, his, lys, arg; Group V (residues influencing chain orientation): gly, pro; and Group VI (aromatic side chains): trp, tyr, phe.
- Conservative substitutions involve substitutions between amino acids in the same class. Non-conservative substitutions constitute exchanging a member of one of these classes for a member of another.
- nucleic acid sequences encode the proteins or polypeptides disclosed herein.
- homologous nucleic acid molecules may comprise a nucleotide sequence that is at least about 90% identical to a reference nucleotide sequence. More preferably, the nucleotide sequence is at least about 95% identical, at least about 97% identical, at least about 98% identical, or at least about 99% identical to a reference nucleotide sequence.
- the homology can be calculated using various, publicly available software tools well known to one of ordinary skill in the art. Exemplary tools include the BLAST system available from the website of the National Center for Biotechnology Information (NCBI) at the National Institutes of Health.
- PCR primers are selected to amplify portions of a nucleic acid sequence of interest, such as a CDR.
- high stringency conditions refers to parameters with which the art is familiar. Nucleic acid hybridization parameters may be found in references that compile such methods, e.g., MOLECULAR CLONING: A LABORATORY MANUAL, J. Sambrook, et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1989), or CURRENT
- vector refers to a nucleic acid molecule that is capable of transporting another nucleic acid.
- Vectors may be, for example, plasmids, cosmids, viruses, or phage.
- An "expression vector” is a vector that is capable of directing the expression of a protein encoded by one or more genes carried by the vector when it is present in the appropriate environment.
- Nucleic acid sequences may be expressed in hosts after the sequences have been operably linked to (i.e., positioned to ensure the functioning of) an expression control sequence.
- These expression vectors are typically replicable in the host organisms, either as episomes or as an integral part of the host chromosomal DNA.
- expression vectors will contain selection markers, e.g., tetracycline or neomycin, to permit detection of those cells transformed with the desired DNA sequences. See, e.g., U.S. Pat. No. 4,704,362, which is incorporated herein by reference.
- the whole antibodies, their dimers, individual light and heavy chains, or other immunoglobulin forms or binding fragments of the present disclosure can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, gel electrophoresis, and the like. See generally, R. Scopes, PROTEIN PURIFICATION, Springer-Verlag, New York (1982). Substantially pure immunoglobulins of at least about 90 to 95% homogeneity are preferred, and 98 to 99% or more homogeneity most preferred, for pharmaceutical uses.
- polypeptides may then be used therapeutically (including extracorporeally) or in developing and performing assay procedures, immunofluorescent stainings, and the like. See generally, IMMUNOLOGICAL METHODS, Vols. I and II, Lefkovits and Pernis, eds., Academic Press, New York, N.Y. (1979 and 1981).
- inhibitors means that the amount is reduced in the presence of a composition as compared with the amount that would occur without the composition.
- competitive inhibitor refers to a molecule that competes with a reference molecule for binding to a target, and thereby blunts, inhibits, dampens, reduces, or blocks the effects of the reference molecule on the target.
- PRO 140 is a competitive inhibitor of CCL5 binding to CCR5 receptor.
- Antist activity refers to the binding by a molecule to a target, wherein the binding activates the target to produce a response.
- CCL5 agonist activity refers to activity consistent with activation by C CL 5.
- “Antagonist activity” as used in the present disclosure refers to the binding by a molecule to a target, wherein the binding does not activate the target to produce a response and the binding blocks the action of one or more agonist molecules.
- “subject” means any animal or artificially modified animal capable of having cancer. Artificially modified animals include, but are not limited to, SCID mice with human immune systems. The animals include but are not limited to mice, rats, dogs, guinea pigs, ferrets, rabbits, and primates. In a preferred embodiment, the subject is a human.
- treating means slowing, stopping, or reversing the progression of a given disease or disorder. In a preferred embodiment,“treating” means reversing the progression of the disease or disorder. In some embodiments, treating includes reversing the progression of the disease or disorder to the point of eliminating the disease or disorder.
- preventing refers to preventing a disease or disorder from occurring; delaying the progression of a disease or disorder; or reducing the pathology or symptomatology of a disease or disorder.
- preventing a cancer includes preventing the development of a tumor, slowing the growth of a tumor, and delaying the development of a tumor.
- administering may be effected or performed using any of the methods known to one skilled in the art.
- the methods may comprise oral, intravenous, intramuscular, or subcutaneous means.
- effective dose means an amount in sufficient quantities to either treat the subject or prevent the subject from developing cancer.
- a person of ordinary skill in the art can perform simple titration experiments to determine what amount is required to treat the subject.
- the present disclosure relates to the use of CCR5 binding agents that target CCR5 receptor, and act as competitive inhibitors to the CCR5 cell receptor without providing CCL5 agonist activity in addition to DNA damaging agents.
- PRO 140 is a humanized monoclonal antibody described in US Pat. Nos. 7,122,185 and 8,821,877, which are incorporated herein by reference, in their entirety.
- PRO 140 is a humanized version of the murine mAh, PA14, which was generated against CD4+ CCR5+ cells. Olson et al., Differential Inhibition of Human Immunodeficiency Virus Type 1 Fusion, gp 120 Binding and CC-Chemokine Activity of Monoclonal Antibodies to CCR5, J. VIROL., 73: 4145-4155. (1999).
- PRO 140 binds to CCR5 expressed on the surface of a cell, and potently inhibits HIV-1 entry and replication at concentrations that do not affect CCR5 chemokine receptor activity in vitro and in the hu-PBL-SCID mouse model of HIV-1 infection. Olson et al., Differential Inhibition of Human
- Nucleic acids encoding heavy and light chains of the humanized PRO 140 antibody have been deposited with the ATCC. Specifically, the plasmids designated pVKHuPRO140, pVg4-HuPRO140 (mut B+D+I) and pVg4-HuPRO140 HG2, respectively, were deposited pursuant to, and in satisfaction of, the requirements of the Budapest Treaty with the ATCC, Manassas, Va., U.S.A. 20108, on Feb. 22,
- ATCC American Type Culture Collection
- the methods disclosed herein comprise
- the PRO 140 comprises (i) two light chains, each light chain comprising the expression product of the plasmid designated pVK:HuPRO140-VK (ATCC Deposit Designation PTA-4097), and (ii) two heavy chains, each heavy chain comprising the expression product of either the plasmid designated pVg4:HuPRO140 HG2-VH (ATCC Deposit Designation PTA-4098) or the plasmid designated pVg4:HuPRO140 (mut B+D+I)-VH (ATCC Deposit Designation PTA-4099).
- the PRO 140 is a humanized or human antibody that binds to the same epitope as that to which antibody PRO 140 binds.
- the monoclonal antibody is the humanized antibody designated PRO 140.
- the present disclosure relates to the use of the human antibody designated CCR5mAb004, or a binding fragment thereof.
- CCR5mAb004 is a fully human mAh, generated using the Abgenix XenoMouse ® technology, that specifically recognizes and binds to CCR5.
- Abgenix XenoMouse ® technology that specifically recognizes and binds to CCR5.
- the present disclosure relates to the use of the monoclonal antibody PA14, produced by the hybridoma cell line designated PA14 (ATCC Accession No. HB-12610), a binding fragment thereof, or an antibody that competes with monoclonal antibody PA- 14 in binding to the CCR5 receptor, in treating or preventing cancer.
- a CCR5 binding agent may comprise a small molecule such as, for example, vicriviroc, UK-427, 857, maraviroc, GW873140, TAK- 652, Takeda AMD070, or the like.
- the antibody or binding fragment thereof comprises a light chain of the antibody. In another embodiment, the antibody or binding fragment thereof comprises a heavy chain of the antibody. In a further embodiment, the antibody or binding fragment thereof comprises an Fab portion of the antibody. In a still further embodiment, the antibody or binding fragment thereof comprises an F(ab')2 portion of the antibody. In an additional embodiment, the antibody or binding fragment thereof comprises an Fd portion of the antibody. In another embodiment, the antibody or binding fragment thereof comprises an Fv portion of the antibody. In a further embodiment, the antibody or binding fragment thereof comprises a variable domain of the antibody. In a still further embodiment, the antibody or binding fragment thereof comprises one or more CDR domains of the antibody. In yet another embodiment, the antibody or binding fragment thereof comprises six CDR domains of the antibody.
- the CC-chemokine receptor CCR5 is the major co-receptor for macrophage-tropic (R5) strains, and plays a crucial role in the sexual transmission of HIV-1. It has been demonstrated that tyrosines and negatively charged residues in the amino-terminal domain (Nt) of CCR5 are essential for gpl20 binding to the co receptor, and for HIV-1 fusion and entry. Residues in the extracellular loops (ECL) 1-3 of CCR5 were dispensable for co-receptor function, yet the CCR5 inter-domain configuration had to be maintained for optimal viral fusion and entry (24).
- ECL extracellular loops
- the G protein coupled receptor CCR5 is normally expressed on a subset of T cells and serves as a co-receptor for HIV infection.
- CCR5 is a requisite fusion co receptor for primary HIV-1 isolates.
- PRO140 is an anti-CCR5 monoclonal antibody that potently inhibits HIV-1 entry and replication at concentrations that do not affect CCR5’s chemokine receptor activity in vitro.
- CCR5 expression is known to increase in a number of cancers (breast cancer (BCa), prostate cancer, colon cancer, melanoma).
- BCa breast cancer
- CCR5 targeted cancer clinical trials using small molecular inhibitors opened to accrual in late 2018.
- CCR5 is expressed in >50% of human BCa, primarily in triple negative BCa.
- CCR5 + BCa epithelial cells have characteristics of cancer stem cells, forming mammospheres and initiating tumors with >60-fold greater efficiency in mice.
- Reintroduction of CCR5 expression into CCR5 negative BCa cells promotes tumor metastases and induces DNA repair gene expression and activity.
- the CCR5 inhibitor leronlimab has been used for treatment of >660 patients with HIV, including meeting its primary endpoints in a phase III study, without significant adverse events reported.
- CCL5 C-C chemokine ligand 5
- RANTES normal T cell expressed and secreted
- the CCR5 receptor is a C-C chemokine G-coupled protein receptor expressed on lymphocytes (e.g., NK cells, B cells), monocytes, macrophages, dendritic cells, a subset of T cells, etc.
- the CCR5 receptor spans the cellular plasma membrane seven times in a serpentine manner.
- the extracellular portions represent potential targets for antibodies targeting CCR5, and comprise an amino-terminal domain (Nt) and three extracellular loops (ECL1, ECL2, and ECL3).
- the extracellular portions of CCR5 comprise just 90 amino acids distributed over four domains. The largest of these domains are at the Nt and ECL2 at approximately 30 amino acids each.
- CCL5 ligand and CCR5 receptor complex causes a conformational change in the receptor that activates the subunits of the G-protein, inducing signaling and leading to changed levels of cyclic AMP (cAMP), inositol triphosphate, intracellular calcium, and tyrosine kinase activation.
- cAMP cyclic AMP
- NF-kB transcription factor
- CCL5 1-15 residue moiety of CCL5 is inserted into the CCR5 binding pocket; the 1-6 N-terminal domain of CCL5 is buried within the transmembrane region of CCR5; and the 7-15 residue moiety of CCL5 is predominantly encompassed by the N-terminal domain and extracellular loops of CCR5.
- CCL5 residues Alal6 and Argl7 and additional residues of the 24-50 residue moiety interact with the upper N-terminal domain and extracellular loop interface of CCR5. It is further reported that the integrity of the amino terminus of CCL5 is crucial to receptor binding and cellular activation. Further, it has been reported that CCL5 and HIV-1 primarily interact with mostly the same CCR5 residues, and share the same chemokine receptor binding pocket.
- CCR5 signaling has anti-tumor effects, acting as a co-stimulatory molecule for T cell activation and increasing T cell chemotaxis to the tumor
- the CCL5/CCR5 axis signaling may be preferentially activated in certain types of cancers, for example breast and prostate cancers, and that such signaling facilitates disease progression.
- Cancer cells may overexpress CCL5, CCR5, or both, likely contributing to their growth and proliferation via the effects of CCR5 signaling on mechanistic target of rapamycin (mTOR). Additionally, some
- immunosuppressive immune cells including regulatory T cells (Treg) and myeloid- derived suppressor cells (MDSC), express CCR5, suggesting another pathway by which CCR5 signaling may contribute to tumor growth.
- Treg regulatory T cells
- MDSC myeloid- derived suppressor cells
- microenvironment can exploit CCL5 production by CD4 + and CD8 + T cells to lead to increased tumor growth and tumor cell spreading.
- PRO 140 (Leronlimab) binds with CCR5 receptor and is known to share some binding commonalities with CCL5. Leronlimab binds CCR5 receptor amino acid residues in EL2 alone or in combination with Nt residues. This binding to the CCR5 receptor binding sites for anti-CCR5 monoclonal antibodies is distinct from those of small-molecule CCR5 binding agents.
- the monoclonal antibody PRO 140 does not affect cAMP levels when added to CD4+ T cells alone, but diminishes the effect of CCL5 on cAMP levels when administered with CCL5.
- PRO 140 alone does not affect chemotaxis of CHO-K1 cells, PRO 140 reduces CCL5- induced chemotaxis when administered with CCL5.
- PRO 140 does not have agonist activity for CCR5 but acts as a competitive inhibitor with CCL5 for binding to CCR5.
- Leronlimab blocks human breast cancer xenograft metastasis in mice. Leronlimab also augmented cell killing by DNA damage inducing agents including Doxorubicin.
- leronlimab binds CCR5 in BCa cells, blocking breast cancer cellular invasion and tumor metastasis, and augmenting cell killing by DNA damage inducing chemotherapies.
- CCR5 augments DNA repair and is expressed selectively on cancerous but not normal breast epithelial cells
- leronlimab may enhance the tumor specific activities of DNA damage response (DDR)-based treatments, allowing a reduction in dose of chemotherapy and radiation.
- DDR DNA damage response
- the studies described herein assess the binding and functional interaction of the humanized monoclonal antibody to CCR5 (Leronlimab) with human breast cancer cell lines.
- the present disclosure provides methods of treating or preventing a cancer comprising administering to a subject in need thereof a competitive inhibitor to a CCR5 cell receptor.
- a method for preventing a cancer is provided.
- the present disclosure provides a method of preventing a cancer comprising administering to a subject in need thereof a competitive inhibitor to a CCR5 cell receptor that does not itself have CCL5 agonist activity is provided, wherein the competitive inhibitor binds to the ECL-2 loop of the CCR5 cell receptor.
- the competitive inhibitor competes with CCL5 for binding to the CCR5 cell receptor.
- the competitive inhibitor comprises the monoclonal antibody PRO 140, or a binding fragment thereof.
- the competitive inhibitor competes for binding with the monoclonal antibody PRO 140, or a binding fragment thereof.
- the present disclosure provides a method of preventing a cancer comprising administering to a subject in need thereof: (a) a PRO 140 antibody, or binding fragment thereof; (b) a nucleic acid encoding a PRO 140 antibody, or binding fragment thereof; (c) a vector comprising a nucleic acid encoding a PRO 140 antibody, or binding fragment thereof; or (d) a host cell comprising (i) a PRO 140 antibody, or binding fragment thereof, (ii) a nucleic acid encoding a PRO 140 antibody, or binding fragment thereof, or (iii) a vector comprising a nucleic acid encoding a PRO 140 antibody, or binding fragment thereof.
- the PRO 140 antibody, or binding fragment thereof may comprise, for example, a PRO 140 monoclonal antibody or a scFv.
- the present disclosure provides a method of preventing a cancer comprising administering to a subject in need thereof a PRO 140 antibody, or binding fragment thereof.
- the competitive inhibitor to a CCR5 cell receptor such as PRO 140, is administered with a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers are well known to those skilled in the art. Such pharmaceutically acceptable carriers may include but are not limited to aqueous or non- aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, saline, and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.
- the dose of the composition of the invention will vary depending on the subject and upon the particular route of administration used. Dosages can range from 0.1 to 100,000 pg/kg. Based upon the composition, the dose can be delivered continuously, such as by continuous pump, or at periodic intervals, e.g., on one or more separate occasions. Desired time intervals of multiple doses of a particular composition can be determined without undue experimentation by one skilled in the art.
- the antibody or binding fragment thereof is administered to the subject a plurality of times and each
- each administration delivers from 0.01 mg per kg body weight to 50 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers from 0.05 mg per kg body weight to 25 mg per kg body weight of the antibody or binding fragment thereof to the subject. In a further embodiment, each administration delivers from 0.1 mg per kg body weight to 10 mg per kg body weight of the antibody or binding fragment thereof to the subject. In a still further embodiment, each administration delivers from 0.5 mg per kg body weight to 5 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers from 1 mg per kg body weight to 3 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers about 2 mg per kg body weight of the antibody or binding fragment thereof to the subject.
- the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of less than one week.
- the first administration is separated from the subsequent administration by an interval of at least one week. In a further embodiment, the first administration is separated from the subsequent administration by an interval of one week. In another embodiment, the first administration is separated from the subsequent administration by an interval of two to four weeks. In another embodiment, the first administration is separated from the subsequent administration by an interval of two weeks. In a further embodiment, the first administration is separated from the subsequent administration by an interval of four weeks. In yet another embodiment, the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of at least one month.
- the antibody or binding fragment thereof is administered to the subject via intravenous infusion. In another embodiment, the antibody or binding fragment thereof is administered to the subject via subcutaneous injection. In another embodiment, the antibody or binding fragment thereof is administered to the subject via intramuscular injection.
- the PRO 140 is administered at a once weekly dose of 350mg to 1400 mg, or about 525 mg or about 700 mg or about 1050 mg. In some embodiments, the PRO 140 is administered at a twice weekly dose of 350mg to 1400 mg, or about 525 mg or about 700 mg or about 1050 mg.
- PRO 140 is administered in a formulation comprising concentrated PRO 140 in an amount greater than about 100 mg/mL and less than about 200 mg/mL; a tonicifier consisting essentially of a sodium salt and a histidine and glycine buffer present in a combined amount of from about 110 mM to about 120 mM and wherein the buffer is present in an amount of about 10 mM to about 25 mM; and a surfactant, wherein the formulation is hypotonic and has a total salt concentration of less than 100 mM.
- a tonicifier consisting essentially of a sodium salt and a histidine and glycine buffer present in a combined amount of from about 110 mM to about 120 mM and wherein the buffer is present in an amount of about 10 mM to about 25 mM
- a surfactant wherein the formulation is hypotonic and has a total salt concentration of less than 100 mM.
- PRO 140 is administered in a formulation comprising: concentrated PRO 140 in an amount greater than about 100 mg/mL and less than about 200 mg/mL; a sodium salt in an amount greater than about 90 mM and less than 100 mM; a histidine and glycine buffer in an amount greater than about 5 mM and less than about 25 mM; a surfactant in an amount greater than about 0.001% w/v and less than about 0.2% w/v; and, optionally, a stabilizing agent or non-salt tonicifier in an amount of about 0.05% w/v to about 1.8% w/v; wherein the formulation has an osmolality of about 250 to about 280 mOsm and has a total salt concentration of less than 100 mM.
- PRO 140 is administered in a low viscosity, hypotonic formulation, comprising: (a) concentrated PRO 140 in an amount greater than about 100 mg/mL and less than about 200 mg/mL; (b) a sodium salt in an amount selected from about 90 mM or about 95 mM; (c) a histidine and glycine buffer in an amount of about 20 mM; (d) a surfactant in an amount of 0.005% to 0.2% w/v; and optionally (e) a stabilizing agent or non-salt tonicifier in an amount sufficient to provide an osmolality of the formulation of about 260-280 mOs/kg; wherein the formulation has a total salt concentration of less than 100 mM.
- PRO 140 is administered in a low viscosity hypotonic formulation, comprising: (a) concentrated PRO 140 in an amount greater than about 100 mg/mL and less than about 200 mg/mL; (b) a salt in an amount selected from about 90 mM or about 95 mM, wherein the salt is selected from sodium chloride, sodium gluconate, or sodium lactate; (c) a histidine and glycine buffer in an amount of about 20 mM; (d) a surfactant in an amount of about 0.005% to about 0.2% w/v, wherein the surfactant is a polysorbate, a poloxamer, or a pluronic; and (e) a stabilizing agent or non-salt tonicifier present in an amount sufficient to provide an osmolality of the formulation of about 230 mOs/kg to about 280 mOs/kg, wherein the stabilizing agent or non-salt tonicifier is selected from a sugar alcohol, a monosaccharide
- PRO 140 is administered in a composition
- a composition comprising PRO 140 in an amount greater than about 100 mg/mL and less than about 200 mg/mL, a tonicifier comprising a sodium salt present in a concentration of greater than about 90 mM and a histidine and glycine buffer present in a combined amount of from 110 mM to 120 mM and a surfactant present in an amount of from about 0.001% to about 0.2% w/v, wherein the composition has an osmolality of about 230 to about 290 mOs/kg and a total salt concentration of less than 100 mM.
- PRO 140 is provided as an article of manufacture comprising a container and a formulation comprising PRO 140 in a concentration of greater than 100 mg/mL and less than 200 mg/mL, a tonicifier of a sodium salt present in a concentration of greater than about 90 mM and a histidine and glycine buffer present in a combined amount of from about 110 mM to about 120 mM and the formulation has a total salt concentration of less than 100 mM, a surfactant in an amount of from about 0.005% to about 0.2%, and instructions for use.
- PRO 140 will be administered in a dose of 700 mg of Leronlimab (PRO 140) (175 mg/mL) delivered as two injections of 2 mL each and administered subcutaneously on opposite sides of the abdomen.
- Each vial of the Leronlimab (PRO 140) product may contain -1.4 mL antibody at a concentration of 175mg/mL.
- a therapeutic agent that is not a CCR5 binding agent may be administered in conventional doses using conventional methods.
- a therapeutic agent that is not a CCR5 binding agent may be administered in lower doses due to synergistic effects achieved by administration of the CCR5 binding agent.
- a CCR5 binding agent such as leronlimab, may be administered together with a non-CCR5 binding agent at the same time or in serial order.
- Administration together may be effectively achieved wherein a subject experiences therapeutic effect for each of the CCR5 binding agent and the non-CCR5 binding agent regardless of the particular dosing regimen or order of introduction of the
- the cancer may be, for example, breast cancer, prostate cancer, colon cancer, melanoma, gastric cancer, ovarian cancer, lung (non-small cell) cancer, pancreatic cancer, sarcoma, or blood cell cancer.
- the cancer is breast cancer.
- the cancer is metastatic breast cancer.
- the present disclosure provides methods of treating or preventing metastatic breast cancer comprising administering to a subject in need thereof a CCR5 binding agent in combination with another therapeutic agent.
- the methods disclosed herein comprise administering leronlimab in combination with a DNA damaging agent, such as, for example, doxorubicin or carboplatin.
- a DNA damaging agent such as, for example, doxorubicin or carboplatin.
- the competitive inhibitor to a CCR5 cell receptor, such as PRO 140 is administered in combination with one or more DNA damaging agents, such as chemotherapeutics which may include but are not limited to: alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine,
- bestrabucil bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKTM; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2',2''-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;
- DMFO difluoromethylornithine
- retinoic acid retinoic acid
- esperamicins retiamicins
- capecitabine retinoic acid
- the metastatic breast cancer comprises metastatic triple negative breast cancer and the method comprises administering leronlimab in combination with doxorubicin, or leronlimab in combination with carboplatin.
- the present disclosure provides a method of treating or preventing CCR5 positive metastatic breast cancer comprising administering to a subject in need thereof an effective amount of a CCR5 binding agent.
- the CCR5 binding agent competes with CCL5 for binding to the CCR5 cell receptor.
- the CCR5 binding agent comprises the monoclonal antibody PA14, leronlimab, or CCR5mAb004, or a binding fragment thereof.
- the competitive inhibitor competes for binding with the monoclonal antibody PA14, leronlimab, or CCR5mAb004, or a binding fragment thereof.
- the present disclosure provides a method of treating or preventing CCR5 positive metastatic breast cancer comprising administering to a subject in need thereof leronlimab, or binding fragment thereof.
- preventing the metastatic breast cancer may comprise slowing the growth or spread of the cancer metastasis or the primary tumor, preventing the formation of a metastatic tumor, or limiting or reducing the growth or size of a metastatic tumor or primary tumor.
- CCR5 binding agent such as leronlimab
- a pharmaceutically acceptable carrier is administered with a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers are well known to those skilled in the art. Such pharmaceutically acceptable carriers may include but are not limited to aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, saline, and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte
- the CCR5 binding agent is provided in a formulation as disclosed in U.S. Patent No. 9,956,165, the contents of which are incorporated here by this reference.
- the dose of the composition of the disclosure will vary depending on the subject and upon the particular route of administration used. Dosages can range from 0.1 to 100,000 pg/kg. Based upon the composition, the dose can be delivered continuously, such as by continuous pump, or at periodic intervals, e.g., on one or more separate occasions. Desired time intervals of multiple doses of a particular composition can be determined without undue experimentation by one skilled in the art.
- the antibody or binding fragment thereof is administered to the subject a plurality of times and each
- each administration delivers from 0.01 mg per kg body weight to 50 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers from 0.05 mg per kg body weight to 25 mg per kg body weight of the antibody or binding fragment thereof to the subject. In a further embodiment, each administration delivers from 0.1 mg per kg body weight to 10 mg per kg body weight of the antibody or binding fragment thereof to the subject. In a still further embodiment, each administration delivers from 0.5 mg per kg body weight to 5 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers from 1 mg per kg body weight to 3 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers about 2 mg per kg body weight of the antibody or binding fragment thereof to the subject.
- Embodiments include dosages in amounts rangeing from about 175 mg to about 1,400 mg, including dosage forms delivering certain amounts of the CCR5 binding agent such as 175 mg, 350 mg, 525 mg, 700 mg, 875 mg, 1050 mg, 1,225 mg, and 1,400 mg.
- the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of less than one week.
- the first administration is separated from the subsequent administration by an interval of at least one week. In a further embodiment, the first administration is separated from the subsequent administration by an interval of one week. In another embodiment, the first administration is separated from the subsequent administration by an interval of two to four weeks. In another embodiment, the first administration is separated from the subsequent administration by an interval of two weeks. In a further embodiment, the first administration is separated from the subsequent administration by an interval of four weeks. In yet another embodiment, the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of at least one month.
- the antibody or binding fragment thereof is administered to the subject via intravenous infusion. In another embodiment, the antibody or binding fragment thereof is administered to the subject via subcutaneous injection. In another embodiment, the antibody or binding fragment thereof is administered to the subject via intramuscular injection.
- the aforementioned methods may further comprise administering to the subject a cellular therapy, e.g., an autologous or allogeneic immunotherapy; a small molecule; a chemotherapeutic agent; or an inhibitor of CCR5/CCL5 signaling.
- a cellular therapy e.g., an autologous or allogeneic immunotherapy; a small molecule; a chemotherapeutic agent; or an inhibitor of CCR5/CCL5 signaling.
- an inhibitor of CCR5/CCL5 signaling is administered, and comprises maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- the competitive inhibitor to a CCR5 cell receptor is administered in combination with one or more other therapeutic molecules or treatment, such a cellular therapy, e.g., an autologous or allogeneic immunotherapy; a small molecule; a chemotherapeutic; or an inhibitor of CCR5/CCL5 signaling, such as maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- a cellular therapy e.g., an autologous or allogeneic immunotherapy
- a small molecule e.g., a chemotherapeutic
- an inhibitor of CCR5/CCL5 signaling such as maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- the methods disclosed herein comprise administering PRO 140 in combination with maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- the CCR5 binding agent such as PRO 140
- one or more chemotherapeutics such as, for example: alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine,
- bestrabucil bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine;
- mitoguazone mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSKTM; razoxane; sizofiran;
- DMFO difluoromethylornithine
- retinoic acid retinoic acid
- esperamicins retiamicins
- capecitabine retinoic acid
- a "small-molecule" CCR5 receptor antagonist includes, for example, a small organic molecule which binds to a CCR5 receptor and inhibits the activity of the receptor.
- the small molecule has a molecular weight less than 1,500 daltons. In another embodiment, the small molecule has a molecular weight less than 600 daltons.
- the CCR5 binding agent such as PRO 140
- the CCR5 binding agent is administered in combination with one or more small molecules, such as SCH-C (Strizki et al., PNAS, 98: 12718-12723 (2001)); SCH-D (SCH 417670; vicriviroc); UK-427, 857 (maraviroc; l-[(4,6-dimethyl-5-pyrimidinyl) carbonyl]-4-[4-[2-methoxy-l(R)-4- (trifluoromethyl)phenyl]ethyl-3(S)-methyl-l-piperazinyli-4-methylpiperidine);
- SCH-C Strizki et al., PNAS, 98: 12718-12723 (2001)
- SCH-D SCH 417670; vicriviroc
- UK-427, 857 maraviroc; l-[(4,6-dimethyl-5-pyrimidinyl) carbonyl]-4-[4-[
- oximino-piperidino-piperidine amides (Palani et al., J. Med. Chem., 45: 3143-3160 (2002)); Sch-351125 and Sch-350634 (Este, Curr. Opin. Investig. Drugs., 3 : 379-383 (2002)); l-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4-[l(S)-[4- (trifluoromethyl)phenyl]ethyl]-l-piperazinyl]-piperidine N1 -oxide (Sch-350634) (Tagat et al., J. Med.
- the CCR5 binding agent such as PRO 140
- the competitive binding agent to a CCR5 cell receptor exhibits synergistic effects when administered in combination with a DNA damaging agent.
- the competitive binding agent to a CCR5 cell receptor such as PRO 140, exhibits synergistic effects when administered in combination with a DNA damaging agent and along side one or more other therapeutic molecules or treatment, such as a cellular therapy, a small molecule, a chemotherapeutic, or an inhibitor of CCR5/CCL5 signaling.
- “Synergy” between two or more agents refers to the combined effect of the agents which is greater than their additive effects. Synergistic, additive, or antagonistic effects between agents may be quantified by analysis of the dose-response curves using the Combination Index (Cl) method.
- a Cl value greater than 1 indicates antagonism; a Cl value equal to 1 indicates an additive effect; and a Cl value less than 1 indicates a synergistic effect.
- the Cl value of a synergistic interaction is less than 0.9.
- the Cl value is less than 0.8.
- the Cl value is less than 0.7.
- preventing the cancer may comprise slowing the growth of the cancer, preventing the formation of a tumor, or limiting or reducing the growth or size of a tumor.
- the competitive inhibitor to a CCR5 cell receptor such as PRO 140, is administered with a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers are well known to those skilled in the art. Such pharmaceutically acceptable carriers may include but are not limited to aqueous or non- aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, saline, and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.
- the dose of the composition of the disclosure will vary depending on the subject and upon the particular route of administration used. Dosages can range from 0.1 to 100,000 pg/kg. Based upon the composition, the dose can be delivered continuously, such as by continuous pump, or at periodic intervals, e.g., on one or more separate occasions. Desired time intervals of multiple doses of a particular composition can be determined without undue experimentation by one skilled in the art.
- the antibody or binding fragment thereof is administered to the subject a plurality of times and each
- each administration delivers from 0.01 mg per kg body weight to 50 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers from 0.05 mg per kg body weight to 25 mg per kg body weight of the antibody or binding fragment thereof to the subject. In a further embodiment, each administration delivers from 0.1 mg per kg body weight to 10 mg per kg body weight of the antibody or binding fragment thereof to the subject. In a still further embodiment, each administration delivers from 0.5 mg per kg body weight to 5 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers from 1 mg per kg body weight to 3 mg per kg body weight of the antibody or binding fragment thereof to the subject. In another embodiment, each administration delivers about 2 mg per kg body weight of the antibody or binding fragment thereof to the subject.
- the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of less than one week.
- the first administration is separated from the subsequent administration by an interval of at least one week. In a further embodiment, the first administration is separated from the subsequent administration by an interval of one week. In another embodiment, the first administration is separated from the subsequent administration by an interval of two to four weeks. In another embodiment, the first administration is separated from the subsequent administration by an interval of two weeks. In a further embodiment, the first administration is separated from the subsequent administration by an interval of four weeks. In yet another embodiment, the antibody or binding fragment thereof is administered a plurality of times, and a first administration is separated from the subsequent administration by an interval of at least one month.
- the antibody or binding fragment thereof is administered to the subject via intravenous infusion. In another embodiment, the antibody or binding fragment thereof is administered to the subject via subcutaneous injection. In another embodiment, the antibody or binding fragment thereof is administered to the subject via intramuscular injection.
- the aforementioned methods may further comprise administering to the subject a cellular therapy, e.g., an autologous or allogeneic immunotherapy; a small molecule; a chemotherapeutic agent; or an inhibitor of CCR5/CCL5 signaling.
- a cellular therapy e.g., an autologous or allogeneic immunotherapy; a small molecule; a chemotherapeutic agent; or an inhibitor of CCR5/CCL5 signaling.
- an inhibitor of CCR5/CCL5 signaling is administered, and comprises maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- the competitive inhibitor to a CCR5 cell receptor is administered in combination with one or more other therapeutic molecules or treatment, such a cellular therapy, e.g., an autologous or allogeneic immunotherapy; a small molecule; a chemotherapeutic; or an inhibitor of CCR5/CCL5 signaling, such as maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- a cellular therapy e.g., an autologous or allogeneic immunotherapy
- a small molecule e.g., a chemotherapeutic
- an inhibitor of CCR5/CCL5 signaling such as maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- the methods disclosed herein comprise administering PRO 140 in combination with maraviroc, vicriviroc, aplaviroc, SCH-C, TAK-779, PA14 antibody, 2D7 antibody, RoAbl3 antibody, RoAbl4 antibody, or 45523 antibody.
- cancers expressing CCR5 may also benefit for the use of leronlimab or other anti-CCR5 agents to block metastasis and/or enhance cell death induced by DNA damaging chemotherapy.
- Such other cancers may include, but are not limited to, one of leukemia cancer, lymphoma cancer, bone and connective tissue sarcoma, brain tumor cancer, breast cancer, adrenal cancer, pancreatic cancer, stomach cancer, colon cancer, prostate cancer, rectal cancer, gallbladder cancer, lung cancer, oral cancer, skin cancer, kidney cancer, and osteogenic sarcoma cancer, and others.
- Anti-CCR5 agents may include, but are not limited to, antibodies, other proteins, and small molecule agents such as, for example, maraviroc and vicriviroc.
- the DNA damaging chemotherapy agent may include, but is not limited to, anthracyclines doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, and ametantrone, and any derivatives thereof.
- chemotherapy agents may be used with the present disclosure, and may benefit from the present disclosure such as, for example, carboplatin, cisplatin, cyclophosphamide, docetaxel, erlotinib, etoposide, fluorouracil, gemcitabine, imatinib mesylate, irinotecan, methotrexate, paclitaxel, sorafmib, sunitinib, topotecan, vincristine or vinblastine, and others. It is contemplated that any conventional therapeutic agents may be used together with the present disclosure, and may benefit from the present disclosure for use in treating cancer, or cancer metastasis.
- DNA damage response is believed to be regulated by two homologous protein kinases, ataxia telangiectasia (ATM) and ataxia telangiectasia Rad3-related (ATR).
- ATR signals to regulate DNA replication, cell cycle transitions, and DNA repair through the phosphorylation of hundreds of substrates, including checkpoint kinase 1 (Chkl).
- DNA- damaging agents have a long history of use in cancer chemotherapy. DNA damage induces apoptosis of cells and is widely believed to be the major antiproliferative mechanism of DNA damaging anticancer drugs.
- FIGS 1 A and IB Leronlimab binds CCR5 in human breast cancer cells.
- a MDA-MB-231 human breast cancer cell line was transfected with a human CCR5 expression vector as a model system.
- a previously tested commercial APC conjugated mouse anti-human/mouse/ rat CCR5 antibody from R&D (FAB1802A) (APC-ocCCR5) was used as a positive control to assess CCR5 positive cells.
- MDA-MB-231-CCR5 cells were stained with both APC- ocCCR5 and leronlimab using the concentration from 1-140 Dg/ml.
- FIG 2A, Figure 2B, Figure 2C, and Figure 2D PROMO (leronlimab) blocks human CCR5-mediated signaling in human breast cancer cells.
- CCR5 activation induces calcium flux (Mueller et al., 2002; Petkovic et ak, 2004).
- To assess the effects of leronlimab on CCR5 function we measured the calcium responses induced by CCL5 in MDA-MB-231-CCR5 cells with or without leronlimab by living cell image ( Figure 2A, Figure 2B, and Figure 2C). Fluo-4 was used as calcium concentration indicator.
- the CCR5 antagonist, vicriviroc was used as positive control ( Figures 2A and 2D).
- FIG. 3A, Figure 3B, Figure 3C, and Figure 3D Leronlimab blocks CCR5 mediated invasion of human breast cancer cells into extracellular matrix.
- the ability of breast cancer cells to invade extra-cellular matrix is distinguishable from but an important step in tumor metastasis (Zetter, 1990).
- MDA-MB-231 cells were used.
- CCL5 was used as chemoattractant to induce invasion.
- FIG. 4 A and Figure 4B Leronlimab block breast cancer metastasis in mice.
- the mice were divided into 4 groups (control, leronlimab, maraviroc and vicriviroc) randomly.
- MDA-MB-231 cells stable transfected with Luc2-GFP was injected into the mice through tail-vein.
- the mice in each group were treated one day before injection.
- the metastasis tumor formed in the lung was determined by bioluminescence imaging.
- the bioluminescence images of the representative mice from control, Leronlimab and Maraviroc group were showed in (Figure 4A).
- the quantitative analysis of tumor size in each group was shown in (Figure 4B).
- FIG. 5 A and Figure 5B Leronlimab enhances the cell death induced by doxorubicin, a DNA damage inducing chemotherapy agent.
- MDA-MB-231 cells were treated with 10 mg/ml of leronlimab combining with different dose of doxorubicin for 3 days.
- the MTT assay was used to determine the relative cell number (Figure 5A).
- Phase lb Described here are interim results from a phase Ib/II study of leronlimab (PRO 140) combined with carboplatin in patients with CCR5+ metastatic Triple Negative Breast Cancer (mTNBC).
- the primary objective of Phase lb is to determine the safety, tolerability and maximum tolerate dose (MTD) of PRO 140 in patients with TNBC, when combined with carboplatin to define a recommended Phase II dose of the combination.
- the primary objective of phase 2b is to evaluate the impact on
- PFS progression-free survival
- a first subject enrolled in the study, subject 706-001, is a 42 year old female with Stage IV metastatic triple negative breast cancer. Subject has a history of left breast cancer with a right lung metastasis.
- the subject was diagnosed with Stage IIA Grade 3 Invasive Ductal Carcinoma (ER neg/PR neg/HER-2-NEU neg. and previously received dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide [ddAC] and Paclitaxel.
- the subject underwent a left lumpectomy of the breast and a sentinel lymph node biopsy three weeks following diagnosis.
- leronlimab 350mg leronlimab (PRO 140) (1).
- Each treatment cycle consisted of 21 days.
- Leronlimab (PRO 140) was administered subcutaneously weekly on Days 1, 8, and 15 in combination with carboplatin AUC 5 on Day 1 of each cycle (every 21 days). This treatment regimen was used for all subjects enrolled in the mTNBC study, unless otherwise indicated.
- CTC circulating tumor cells
- CAML cancer associated macrophage-like cells
- Creatv Microtech has developed a size based technology and detection methodology (LifeTrac Assay) that enables the collection and characterization of all cancer associated cells in the blood i.e., CTCs, epithelial mesenchymal transition cells (EMTs) and CAMLs. [Adams Cytometry 2015, Adams RSC 2014] The CellSieveTM filtration platform is used to capture CAMLs and CTCs.
- CAML- Total 2 1 3 1 3 8 Scans were taken at the end of every two cycles (every 6 weeks).
- the subject had Scan 1 after six weeks, a Scan 2 after 12 weeks, and Scan 3 after 18 weeks (Table 4).
- Scan 3 At scan 3, there were no new lung nodules found.
- the target lesion found on the right upper lobe of the lung nodule measured 2.1x1.6 cm, which was previously 2.4x1.9, had a 20% decrease in size.
- a second subject with mTNBC was enrolled in the mTNBC study.
- Data collected from the second patient enrolled in the Company’s mTNBC Phase lb/2 trial showed no detectable levels of CTC after two weeks of treatment with the previously described treatment regimen of leronlimab in combination with carboplatin.
- This patient also showed a 70% reduction in EMT cells after just two weeks of treatment.
- Initial data from the second patient in the mTNBC trial indicated the CTC dropped to zero after two weeks of treatment with leronlimab. Additionally, the second patient had an initial CAML count of 45, and following at least two weeks of treatment the CAML count decreased to 30.
- a third subject was enrolled in the mTNBC study.
- CTC+EMT counts were measured at initiation of treatment and two weeks following initiation of treatment with the previously described treatment regimen. The results indicate that the third patient’s total CTC+EMT counts decreased by 75% during the first two weeks of treatment.
Abstract
Description
Claims
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AU2020254692A AU2020254692A1 (en) | 2019-04-01 | 2020-04-01 | Anti-CCR5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by DNA damaging chemotherapy |
JP2021558834A JP2022527966A (en) | 2019-04-01 | 2020-04-01 | Anti-CCR5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by DNA-damaging chemotherapy |
CN202080035428.3A CN114729023A (en) | 2019-04-01 | 2020-04-01 | anti-CCR5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by DNA damage chemotherapy |
MX2021012011A MX2021012011A (en) | 2019-04-01 | 2020-04-01 | Anti-ccr5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by dna damaging chemotherapy. |
EP20783110.8A EP3947431A4 (en) | 2019-04-01 | 2020-04-01 | Anti-ccr5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by dna damaging chemotherapy |
US17/598,650 US20220162327A1 (en) | 2019-04-01 | 2020-04-01 | Anti-ccr5 agents and methods of treatment that block cancer metastasis or enhance cell death induced by dna damaging chemotherapy |
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"Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ mTNBC", 12 February 2019 (2019-02-12), XP055745288, Retrieved from the Internet <URL:https://ciinicaitrials.gov/ct2/show/NCT03838367> * |
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