WO2017184534A1 - Procédés et compositions destinés à améliorer la sécurité et l'efficacité d'une immunothérapie par cellules tueuses naturelles - Google Patents

Procédés et compositions destinés à améliorer la sécurité et l'efficacité d'une immunothérapie par cellules tueuses naturelles Download PDF

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WO2017184534A1
WO2017184534A1 PCT/US2017/028016 US2017028016W WO2017184534A1 WO 2017184534 A1 WO2017184534 A1 WO 2017184534A1 US 2017028016 W US2017028016 W US 2017028016W WO 2017184534 A1 WO2017184534 A1 WO 2017184534A1
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antibody
cells
cancer
composition
fugetactic
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Michael Callahan
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Gorlin Cos
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Gorlin Cos
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/15—Natural-killer [NK] cells; Natural-killer T [NKT] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/428—Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/10—Inactivation or decontamination of a medicinal preparation prior to administration to an animal or a person
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells

Definitions

  • Natural killer (NK) cells are cytotoxic lymphocytes that are involved in the innate immune system. NK cells can target multiple aberrant cell types and stressed cells, including cancer cells, virus-infected cells, microorganisms, and microorganism-infected cells. NK cells are cytotoxic and can induce apoptosis or osmotic cell lysis in target cells.
  • NK cells may be isolated from the patient (autologous) or from a different source (allogenic).
  • the cells may be expanded and optionally modified before administration to the patient, e.g. by insertion of a gene that confers an advantage on the NK cells, such as a gene expressing a cytokine, Fc receptor, and/or chimeric antigen receptor.
  • NK cell lines have been developed that have shown potential in immunotherapy for numerous diseases, including the NK-92 cell line.
  • NK-92 cells were derived from a patient having NK cell lymphoma.
  • the NK-92 cell line is an immortalized cell line that is capable of genetic modification as well as expansion in vitro. Further information on NK-92 cells, modifications thereof, and uses thereof can be found, for example, in U.S. Patent Nos. 8,313,943; 8,034,332; and U.S. Patent Pub. Nos. 2006/0110360; 2016/0075784; each of which is incorporated herein by reference in its entirety.
  • This invention relates to compositions and methods of making or using of NK-92 cells expressing a high affinity Fc receptor (e.g., high-affinity CD16) or other antibody binding moiety (referred to herein as haNK-92) and bound to an antibody having a high affinity for the Fc receptor (or other moiety), where the antibody is bound to the antibody binding moiety in vitro (i.e., prior to administration to a patient) to produce modified haNK- 92 cells.
  • the cells are optionally pretreated with AMD3100 or other anti-fugetactic agent prior to or after forming the antibody- K-92 complex, such that the anti-fugetactic agent is bound to the cells, e.g.
  • haNK-92 cells via CXCR4 receptors on the surface of the haNK-92 cells.
  • binding of the antibody to the haNK-92 cells prior to administration to a patient reduces the risk of undesired endogenous antibody binding to the haNK-92 cell, for example by autoimmune antibodies produced by the patient.
  • the haNK-92 cells are irradiated (before or after modification).
  • haNK-92 cells have a finite half-life in vivo due to required irradiation prior to administration to a patient. This limits their potential for sustained efficacy even when used contemporaneously or sequentially with an additional agent, such as the modified haNK-92 described herein, with or without the anti-fugetactic agent.
  • the half-life is measured as the time period during which modified haNK-92 cells exhibit antibody-dependent cell-mediated cytotoxicity (ADCC) activity.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • haNK-92 cell half-life is really two different times - a first half-life during which the cells exhibit ADCC properties (half-life with ADCC) and a second half-life measured from the time of injection to cell death including the period extending from loss of ADCC properties to cell death (half-life with ADCC and without ADCC). It is contemplated that during the haNK-92 half-life with ADCC, the extent of ADCC exhibited by these cells is declining as they approach the stage where these cells no longer exhibit ADCC. This means that the efficacy of these cells is front-loaded, with tailing properties during their short lifespan.
  • This invention is further directed to a contemplated synergy between using an albumin complex of an antibody (such as rituximab) and optionally a chemotherapeutic agent associated with the albumin, and the same antibody bound to the modified haNK-92 cells.
  • an albumin complex of an antibody such as rituximab
  • a chemotherapeutic agent associated with the albumin such as rituximab
  • these cells are optionally pretreated with AMD3100 or other anti-fugetactic agent prior to or after forming the antibody-haNK complex.
  • the haNK-92 cells are irradiated (before or after modification).
  • an aqueous composition suitable for in vivo injection into a subject comprising an effective amount of NK-92 cells, wherein said cells comprise a monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection.
  • the antibody has a high affinity for the antibody binding motif.
  • an anti-fugetactic agent is bound to a receptor on the cells.
  • the anti-fugetactic agent is AMD3100, KRH-1636, T-20, T-22, T-140, TE- 14011, T-14012, TN14003, TAK-779, AK602, SCH-351125, Tannic acid, NSC 651016, thalidomide, GF 10923 OX, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine.
  • the receptor is a CXCR4 receptor or a CXCR7 receptor.
  • the antibody binding motif is CD 16 or CD 19. In one embodiment, the antibody binding motif is CD 16 or CD 19. In one
  • the CD 16 is a high-affinity CD 16.
  • the antibody has an affinity for the antibody binding motif of at least 10 5 M "1 . In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10 6 M “1 . In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10 7 M "1 . In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10 8 M “1 . In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10 9 M "1 . In one embodiment, the antibody has an affinity for the antibody binding motif of at least 10 10 M "1 .
  • the antibody is not a therapeutic antibody. That is, in some embodiments, the antibody bound to the haNK-92 cells has no effect on a target cell on its own, but rather serves to direct the modified haNK-92 cells to the target cell. Without being bound by theory, it is contemplated that antibodies with proven safety and antigen binding, but little to no therapeutic effect, may be used in the compositions and methods described herein.
  • the composition further comprises antibody that is not bound to the antibody binding motif. That is, the composition includes excess antibody beyond what is required to fully occupy the antibody binding motifs on the surfaces of the K-92 cells within the composition.
  • the haNK-92 cells may proliferate between the time of binding the antibody to the cells and administration to the patient, e.g., during transport. The presence of excess antibody allows antibody-binding moieties on the progeny haNK-92 cells to bind the antibody and reduces the occurrence of unbound moiety.
  • the presence of unbound antibody in the composition may allow for steady-state binding of the antibody to the cells.
  • a method for treating cancer in a patient in need thereof comprising administering to said patient an effective amount of an NK-92 cell composition, said composition comprising NK-92 cells comprising a monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection.
  • the antibody has a high affinity for the antibody binding motif.
  • a method for treating cancer in a patient comprises administering to said patient a combination of immunotherapy and chemotherapy, wherein said immunotherapy comprises administering to said patient an effective amount of an NK-92 cell composition, said composition comprising NK-92 cells comprising a monoclonal antibody bound thereto through an antibody binding motif on the surface of said cells, and further wherein said cells have been exposed to a sufficient amount of irradiation so as to have a finite lifespan, thereby rendering said composition suitable for in vivo injection; and said chemotherapy comprises administering to said patient a protein carrier having a plurality of said monoclonal antibodies complexed thereto, said protein carrier further comprising a chemotherapeutic agent associated therewith.
  • the antibody has a high affinity for the antibody binding motif.
  • the combination is administered concurrently. In one embodiment, the combination is administered sequentially.
  • the chemotherapeutic agent is paclitaxel. In another preferred embodiment, the protein carrier is albumin.
  • the method further comprises administering an anti -fugetactic agent to the patient. In one embodiment, the anti-fugetactic agent is administered prior to, concurrently with, and/or after administration of the modified NK-92 cells. In one embodiment, the anti-fugetactic agent is bound to a receptor on the cells prior to
  • the anti-fugetactic agent is AMD3100, KRH-1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK-779, AK602, SCH- 351125, Tannic acid, NSC 651016, thalidomide, GF 109230X, an antibody that interferes with dimerization of a fugetactic chemokine, or an antibody that interferes with dimerization of a receptor for a fugetactic chemokine.
  • the method further comprises administering a particle comprising a carrier protein core having the monoclonal antibody associated with the protein core, and optionally comprising a chemotherapeutic agent associated with the core.
  • a particle comprising a carrier protein core having the monoclonal antibody associated with the protein core, and optionally comprising a chemotherapeutic agent associated with the core.
  • the carrier protein is albumin.
  • the albumin is human serum albumin (HSA).
  • the chemotherapeutic agent is paclitaxel.
  • the antibody binding motif is a cell surface receptor.
  • the cell surface receptor is CD 16 or CD 19.
  • the CD 16 is a high-affinity CD 16.
  • the antibody has an affinity for the antibody binding motif of at least 10 6 M "1 .
  • the antibody recognizes a tumor-associated epitope.
  • a method of making an NK-92 composition that is suitable for in vivo injection into a patient, the method comprising:
  • NK-92 cells having an antibody binding motif on the surface of said cells
  • a first subset of the antibody is bound to the antibody binding motif and a second subset of the antibody is not bound to the antibody binding motif.
  • the term "about" when used with regard to a dose amount means that the dose may vary by +/- 10%.
  • compositions and methods include the recited elements, but not excluding others.
  • Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • Consisting of shall mean excluding substantial method steps and more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this invention.
  • “Pharmaceutically acceptable” excipients are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed.
  • antibody refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules (i.e., molecules that contain an antigen binding site that immuno-specifically bind an antigen).
  • the term also refers to antibodies comprised of two immunoglobulin heavy chains and two immunoglobulin light chains as well as a variety of forms including full length antibodies and portions thereof; including, for example, an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab', a F(ab')2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody (dAb), a diabody, a multispecific antibody, a dual specific antibody, an anti -idiotypic antibody, a bispecific antibody, a functionally active epitope-binding fragment thereof, bifunctional hybrid antibodies (e.g., Lanzavecchia et al., Eur.
  • the antibody may be of any type (e.g., IgG, IgA, IgM, IgE or IgD). Preferably, the antibody is IgG. More preferably, the antibody contains a Fc domain.
  • An antibody may be non-human (e.g., from mouse, goat, or any other animal), fully human, humanized, or chimeric.
  • antigen is well understood in the art and includes substances which are immunogenic. As used herein, the term “antigen” may also refer to a substance to which a binding agent other than an antibody (e.g., an aptamer) can bind.
  • biosimilar refers to a biopharmaceutical which is deemed to be comparable in quality, safety, and efficacy to a reference product marketed by an innovator company.
  • carrier protein refers to proteins that function to transport therapeutic agents, antibodies, or both. Examples of carrier proteins are discussed in more detail below. Where albumin is recited herein as the carrier protein, it is contemplated that a different carrier protein can be substituted.
  • dose refers to an amount of therapeutic agent (e.g., cells, binding agent, or chemotherapeutic agent) given to a patient in need thereof.
  • therapeutic agent e.g., cells, binding agent, or chemotherapeutic agent
  • unit dose refers to a dose of the agent that is given to the patient to provide a desired result. In some instances, the unit dose is sold in a sub-therapeutic formulation (e.g., 10% of the therapeutic dose).
  • the unit dose may be administered as a single dose or a series of subdoses.
  • an "effective amount” intends to indicate the amount of a compound or agent (e.g., modified haNK-92 cells) administered or delivered to the patient which is most likely to result in the desired treatment outcome.
  • the amount is empirically determined by the patient's clinical parameters including, but not limited to the stage of disease, age, gender, histology, and likelihood for recurrence.
  • the level of circulating antigen can be used to empirically determine the effective amount of the chemotherapeutic and/or binding agent to administer to a patient.
  • nanoparticle refers to particles with at least one dimension less than 5 microns. In some embodiments, the nanoparticle is less than 1 micron. For direct administration, the nanoparticle may be larger. Even larger particles are expressly
  • conjugate and “complex” as used herein are synonymous with “nanoparticle.”
  • nanoparticle may also encompass discrete multimers of smaller unit nanoparticles.
  • D50 is the particle size below which 50% of the particles fall. 10% of particles are smaller than the D 10 value and 90% of particles are smaller than D90. Where unclear, the "average" size is equivalent to D50.
  • the term "therapeutic effect” refers to achievement of the desired and/or beneficial consequences of a medical treatment.
  • a non-limiting example of a therapeutic effect of the present disclosure is the shrinkage and/or eradication of a tumor and/or killing of cancer cells in a patient.
  • treating covers the treatment of a disease or disorder (e.g., cancer), in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disease or disorder; (iii) slowing progression of the disease or disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • “treating” or “treatment” refers to the killing of cancer cells.
  • treating or “treatment” refers to increasing progression-free survival of the patient(s).
  • treating or “treatment” refers to increasing survival rates.
  • Cytokine is a generic term for non-antibody, soluble proteins which are released from one cell subpopulation and which act as intercellular mediators, for example, in the generation or regulation of an immune response. See Human Cytokines: Handbook for Basic & Clinical Research (Agrawal, et al. eds., Blackwell Scientific, Boston, Mass. 1991) (which is hereby incorporated by reference in its entirety for all purposes).
  • CXCR4/CXCL12 antagonist refers to a compound that antagonizes CXCL12 binding to CXCR4 or otherwise reduces the fugetactic effect of CXCL12.
  • Frugetactic activity or "fugetactic effect” refers to the ability of an agent to repel (or chemorepel) a eukaryotic cell with migratory capacity ⁇ i.e., a cell that can move away from a repellant stimulus). Accordingly, an agent with fugetactic activity is a "fugetactic agent.” Such activity can be detected using any of a variety of systems well known in the art ⁇ see, e.g., U.S. Pat. No. 5,514,555 and U.S. Patent Application Pub. No. 2008/0300165, each of which is incorporated by reference herein in its entirety).
  • anti-fugetactic effect refers to the effect of the anti-fugetactic agent to attenuate or eliminate the fugetactic effect of the chemokine. Accordingly, an agent with anti-fugetactic effect is a "anti-fugetactic agent.”
  • NK-92 cells can be modified by any method to produce haNK-92 cells, i.e., NK-92 cells expressing a high-affinity antibody binding motif on the surface of the cells. See, e.g., U.S. Patent Nos. 8,313,943; 8,034,332; and U.S. Patent Pub. Nos. 2006/0110360;
  • the haNK-92 cells express CD 16, and particularly high affinity CD 16. In some embodiments, the haNK-92 cells express CD 19.
  • the haNK-92 cells are modified by contacting the cells with the antibody under conditions to allow binding of the antibody to the antibody binding motif.
  • the haNK-92 cells are optionally contacted with an anti-fugetactic agent under conditions to allow binding of the anti-fugetactic agent to a receptor (e.g., CXCR4 or CXCR7) on the surface of the haNK-92 cell.
  • a receptor e.g., CXCR4 or CXCR7
  • the anti-fugetactic agent is administered to the patient in conjunction with the modified haNK-92 cells. In some embodiments, the anti-fugetactic agent is administered prior to administration of the modified haNK-92 cells. In some embodiments, the anti-fugetactic agent is administered at the same time (but not necessarily via the same route of administration) as the modified haNK-92 cells.
  • the haNK-92 cells are irradiated before administration to the patient.
  • Such irradiation may occur prior to or after contacting the cells with the antibody.
  • Such irradiation may occur prior to or after contacting the cells with the anti-fugetactic agent.
  • Table 1 depicts a list of non-limiting list of antibodies for cancer targets.
  • Table 1 Antibodies for cancer targets
  • the antibody is selected from the group consisting of ado- trastuzumab emtansine, alemtuzumab, bevacizumab, blinatumomab, brentuximab vedotin, cetuximab, denosumab, dinutuximab, ibritumomab tiuxetan, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, rituximab, trastuzumab, or any biosimilar thereof.
  • the antibody is a non-therapeutic and non-endogenous human antibody. In some embodiments, the antibody is a chimeric antibody, a non-endogenous human antibody, a humanized antibody, or non-human antibody.
  • the mammal Before administering modified haNK-92 cells as provided herein to a mammal, the mammal can be assessed to determine whether or not the mammal has a cancer or disease expressing the relevant antigen (e.g., the antigen recognized by the antibody bound to the haNK-92 cells). Any appropriate method can be used to determine whether or not a mammal has a cancer or disease expressing the relevant antigen.
  • a mammal e.g., human
  • a tissue biopsy can be collected and analyzed to determine whether or not a mammal has a cancer or disease expressing the antigen.
  • the mammal can be administered modified haNK-92 cells as provided herein.
  • the cells can be administered prior to or in lieu of surgical resection of a tumor.
  • the cells as provided herein can be administered following resection of a tumor.
  • the modified haNK-92 cells as provided herein can be administered to a mammal in any appropriate amount, at any appropriate frequency, and for any appropriate duration effective to achieve a desired outcome (e.g., to increase progression-free survival).
  • cells as provided herein can be administered to a mammal having a cancer or disease to reduce the progression rate of the cancer or disease by 5, 10, 25, 50, 75, 100, or more percent.
  • the progression rate can be reduced such that no additional cancer progression is detected.
  • the modified ha K-92 cells (and any other agent as described herein) may be provided as a pharmaceutically acceptable composition.
  • a pharmaceutically acceptable composition may comprise one or more pharmaceutically acceptable excipients.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Liquid pharmaceutical compositions include, for example, solutions, suspensions, and emulsions suitable for intradermal, subcutaneous, parenteral, or intravenous administration.
  • Sterile water solutions of the modified NK cell compositions or sterile solutions of the modified NK cell compositions in solvents comprising water, buffered water, saline, PBS, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, detergents, and the like.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in
  • compositions of the present invention can be administered by various routes, e.g., subcutaneous, intradermal, transdermal, intramuscular, intravenous, or intraperitoneal.
  • Antibody complexes with albumin particles carrying a cytotoxic agent have tumor targeting capacity that translates into better delivery of the cytotoxic agent to the tumor. These complexes are not irradiated. As such, these complexes are not subject to loss of activity due to cellular death. Antibody complexes remaining in the body during their half- life are contemplated to be as active as those immediately after injection.
  • modified haNK-92 cells are administered either before or after the albumin-antibody complex.
  • modified haNK-92 cells are administered first, one can either contemporaneously administered the albumin- antibody complex or wait for a period of time after modified haNK-92 cells have been administered.
  • the period of time is within hours so that as the modified haNK-92 lose efficacy, the albumin-antibody complex replaces that lost efficacy.
  • the albumin-antibody complex is administered 3 or more days after modified haNK-92 so that there is little to no contribution from one therapy with the other. Which therapy that is initiated first is within the decision of the attending clinician.
  • modified haNK-92 cells as described herein may advantageously be administered after the albumin-antibody complex so as to reduce the risk of renal damage due to clearance of dead cells arising from both dead tumor cells and dead haNK-92 cells.
  • the combined treatment also provides an additional challenge to the tumor and reduces the ability of the tumor to become resistant to the combined treatment.
  • modified haNK-92 plus the fugetactic agent
  • the antibody- albumin complexes allow for both high initial tumor cell killing by the components (e.g., because the AMD-bound modified haNK-92 can pass the fugetactic wall) and long-term tumor cell killing with the antibody-albumin complex, thereby providing a one-two punch to the tumor.
  • This binary approach is contemplated to result in a synergy between the two components as it allows for the short term killing by AMD-bound modified haNK-92 coupled with both the short term and long term killing of the antibody-albumin complex (e.g., AR160) against tumors (e.g., CD20+ lymphomas).
  • the antibody is one of the antibodies listed in Table 1.
  • the chemotherapeutic is selected from the group consisting of abiraterone, bendamustine, bortezomib, carboplatin, cabazitaxel, cisplatin, chlorambucil, dasatinib, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everolimus, gefitinib, idarubicin, imatinib, hydroxyurea, imatinib, lapatinib, leuprorelin, melphalan, methotrexate, mitoxantrone, nedaplatin, nilotinib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, picoplatin, romidepsin, satraplatin, sorafenib, vemurafenib, sunitinib, tenipos
  • ABRAXANE® and albumin particles comprising other chemotherapeutic agents are disclosed by U.S. Patent Nos. 7,758,891; 7,820,788; 7,923,536; 8,034,375; 8,138,229; 8,268,348; 8,314, 156; 8,853,260; and 9, 101,543, each of which is incorporated herein by reference in its entirety.
  • carrier protein, chemotherapeutic, antibody conjugates, or combinations thereof are disclosed by PCT Publication Nos. WO2016/057554,
  • Table 2 depicts a list of non-limiting list of chemotherapeutic agents. It should be understood, that while targets are limited, the use of the agents is not limited only to the listed targets. It is contemplated that each individually can be used for any type of cancer, including those listed throughout the disclosure.
  • ABVD Adriamycin, bleomycin, vinblastine Hodgkin lymphoma
  • ABVE Adriamycin, bleomycin, vincristine Hodgkin lymphoma (in children)
  • AC-T (Adriamycin, cylclophosphamide, Breast cancer
  • Adcetris (Brentuximab Vedotin) Anaplastic large cell lymphoma; Hodgkin lymphoma
  • ADE Cytarabine (Ara-C), Daunorubicin Acute myeloid leukemia (in children) Hydrochloride, Etoposide)
  • Adriamycin Doxorubicin Hydrochloride
  • Acute lymphoblastic leukemia acute myeloid leukemia; breast cancer, gastric (stomach) cancer; Hodgkin lymphoma; neuroblastoma; non-Hodgkin lymphoma; ovarian cancer; small cell lung cancer; soft tissue and bone sarcomas; thyroid cancer; transitional cell bladder cancer; Wilms tumor
  • Adrucil Basal cell carcinoma; breast cancer; colorectal cancer; gastric (stomach) adenocarcinoma; pancreatic cancer; squamous cell carcinoma of the head and neck
  • Alimta (Pemetrexed Disodium) Malignant pleural mesothelioma; non-small cell lung cancer
  • Ambochlorin Chronic lymphocytic leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma
  • Aromasin (Exemestane) Advanced breast cancer Advanced breast cancer; early-stage breast cancer and estrogen receptor positive
  • Arranon (Nelarabine) T-cell acute lymphoblastic leukemia; T-cell lymphoblastic lymphoma
  • BiCNU Carmustine Brain tumors; Hodgkin lymphoma; multiple myeloma; non-Hodgkin lymphoma
  • lymphoma penile cancer
  • squamous cell carcinoma of the cervix squamous cell carcinoma of the head and neck
  • squamous cell carcinoma of the vulva testicular cancer
  • Busulfex (Busulfan) Chronic myelogenous leukemia
  • Cerubidine (Daunorubicin Hydrochloride) Acute lymphoblastic leukemia; acute myeloid leukemia
  • Cisplatin Bladder cancer cervical cancer; malignant mesothelioma; non-small cell lung cancer; ovarian cancer; squamous cell carcinoma of the head and neck; testicular cancer
  • Clafen (Cyclophosphamide) Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; multiple myeloma; mycosis fungoides; neuroblastoma; non- Hodgkin lymphoma; ovarian cancer;
  • Clofarex (Clofarabine) Acute lymphoblastic leukemia
  • Cosmegen (Dactinomycin) Ewing sarcoma; gestational trophoblastic disease; rhabdomyosarcoma; solid tumors;
  • Cyclophosphamide Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; multiple myeloma; mycosis fungoides; neuroblastoma; non- Hodgkin lymphoma; ovarian cancer;
  • Cyramza (Ramucirumab) Adenocarcinoma; colorectal cancer; non- small cell lung cancer
  • Cytarabine Acute lymphoblastic leukemia; acute myeloid leukemia; chronic myelogenous leukemia; meningeal leukemia
  • Cytosar-U (Cytarabine) Acute lymphoblastic leukemia; acute myeloid leukemia; chronic myelogenous leukemia; meningeal leukemia
  • Cytoxan (Cyclophosphamide) Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; chronic lymphocytic leukemia; chronic myelogenous leukemia; Hodgkin lymphoma; multiple myeloma; mycosis fungoides; neuroblastoma; non- Hodgkin lymphoma; ovarian cancer;
  • Dactinomycin Ewing sarcoma gestational trophoblastic disease; rhabdomyosarcoma; solid tumors; testicular cancer; Wilms tumor
  • Daunorubicin Hydrochloride Acute lymphoblastic leukemia; acute myeloid leukemia
  • Denosumab Giant cell tumor of the bone breast cancer, prostate cancer
  • stomach or gastroesophageal junction non- small cell lung cancer; prostate cancer;
  • Doxil Doxorubicin Hydrochloride AIDS-related Kaposi sarcoma; multiple Liposome myeloma; ovarian cancer
  • Doxorubicin Hydrochloride Acute lymphoblastic leukemia; acute myeloid leukemia; breast cancer; gastric (stomach) cancer; Hodgkin lymphoma; neuroblastoma; non-Hodgkin lymphoma; ovarian cancer; small cell lung cancer; soft tissue and bone sarcomas; thyroid cancer; transitional cell bladder cancer; Wilms tumor.
  • Dox-SL Doxorubicin Hydrochloride AIDS-related Kaposi sarcoma
  • Liposome myeloma; ovarian cancer
  • DTIC-Dome Hodgkin lymphoma; melanoma
  • Efudex Basal cell carcinoma; breast cancer; colorectal cancer; gastric (stomach) adenocarcinoma; pancreatic cancer; squamous cell carcinoma of the head and neck
  • Eloxatin (Oxaliplatin) Colorectal cancer; stage III colon cancer
  • Erbitux Colorectal cancer; squamous cell carcinoma of the head and neck
  • Etopophos Small cell lung cancer; testicular cancer
  • Liposome myeloma; ovarian cancer
  • Everolimus Breast cancer pancreatic cancer; renal cell carcinoma; subependymal giant cell astrocytoma
  • Fludara Fredarabine Phosphate
  • Chronic lymphocytic leukemia Fluoroplex Fluoroplex (Fluorouracil) Basal cell carcinoma; breast cancer; colorectal cancer; gastric (stomach) adenocarcinoma; pancreatic cancer; squamous cell carcinoma of the head and neck
  • Folex Acute lymphoblastic leukemia; breast cancer;
  • gestational trophoblastic disease head and neck cancer; lung cancer; mycosis fungoides; non-Hodgkin lymphoma; osteosarcoma
  • FU-LV Colorectal cancer esophageal cancer
  • gastric cancer esophageal cancer
  • pancreatic cancer ovarian cancer; pancreatic cancer
  • GEMCITABINE-CISPLATIN Biliary tract cancer bladder cancer; cervical cancer; malignant mesothelioma; non-small cell lung cancer; ovarian cancer; pancreatic cancer
  • Gemzar (Gemcitabine Hydrochloride) Breast cancer; non-small cell lung cancer;
  • pancreatic cancer ovarian cancer; pancreatic cancer
  • Gleevec (Imatinib Mesylate) Acute lymphoblastic leukemia; chronic myeloblastic leukemia
  • eosinophilic leukemia or hypereosinophilic syndrome eosinophilic leukemia or hypereosinophilic syndrome
  • chronic myelogenous leukemia eosinophilic leukemia or hypereosinophilic syndrome
  • dermatofibrosarcoma protuberans eosinophilic leukemia or hypereosinophilic syndrome
  • chronic myelogenous leukemia eosinophilic leukemia or hypereosinophilic syndrome
  • chronic myelogenous leukemia dermatofibrosarcoma protuberans
  • myelodysplastic/myeloproliferative neoplasms myelodysplastic/myeloproliferative neoplasms; systemic mastocytosis.
  • Gliadel Carmustine Implant
  • Glioblastoma multiforme malignant glioma
  • Hycamtin Topotecan Hydrochloride Cervical cancer; ovarian cancer; small cell lung cancer
  • Hyper-CVAD Acute lymphoblastic leukemia; non-Hodgkin lymphoma
  • Ibrutinib Chronic lymphocytic leukemia; mantel cell lymphoma;
  • Iclusig Ponatinib Hydrochloride Acute lymphoblastic leukemia; Chronic myelogenous leukemia
  • Idamycin (Idarubicin Hydrochloride) Acute myeloid leukemia
  • Imatinib Mesylate Acute lymphoblastic leukemia; chronic
  • eosinophilic leukemia or hypereosinophilic syndrome eosinophilic leukemia or hypereosinophilic syndrome
  • chronic myelogenous leukemia eosinophilic leukemia or hypereosinophilic syndrome
  • dermatofibrosarcoma protuberans eosinophilic leukemia or hypereosinophilic syndrome
  • chronic myelogenous leukemia eosinophilic leukemia or hypereosinophilic syndrome
  • chronic myelogenous leukemia dermatofibrosarcoma protuberans
  • myelodysplastic/myeloproliferative neoplasms myelodysplastic/myeloproliferative neoplasms; systemic mastocytosis.
  • Imbruvica (Ibrutinib) Chronic lymphocytic leukemia; mantle cell lymphoma; Waldenstrom macroglobulinemia
  • Leukeran Chronic lymphocytic leukemia; Hodgkin lymphoma; non-Hodgkin lymphoma
  • Linfolizin Chlorambucil
  • Hodgkin lymphoma Hodgkin lymphoma
  • non-Hodgkin lymphoma Hodgkin lymphoma
  • LipoDox Doxorubicin Hydrochloride AIDS-related Kaposi sarcoma; multiple Liposome
  • myeloma ovarian cancer
  • lymphocytic leukemia chronic myelogenous leukemia
  • Hodgkin lymphoma malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion
  • mycosis fungoides non-Hodgkin lymphoma
  • Mekinist (Trametinib) Melanoma Mercaptopurine Acute lymphoblastic leukemia
  • Methazolastone (Temozolomide) Anaplastic astrocytoma; glioblastoma
  • Mexate Acute lymphoblastic leukemia; breast cancer;
  • gestational trophoblastic disease head and neck cancer; lung cancer; mycosis fungoides; non-Hodgkin lymphoma; osteosarcoma
  • Mexate-AQ Acute lymphoblastic leukemia; breast cancer;
  • gestational trophoblastic disease head and neck cancer; lung cancer; mycosis fungoides; non-Hodgkin lymphoma; osteosarcoma
  • Mitozytrex Mitomycin C
  • Gastric stomach
  • pancreatic pancreatic
  • lymphocytic leukemia chronic myelogenous leukemia
  • Hodgkin lymphoma malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion
  • mycosis fungoides non-Hodgkin lymphoma
  • Mylotarg (Gemtuzumab Ozogamicin) Acute myeloid leukemia
  • Nanoparticle Paclitaxel (Paclitaxel Albumin- Breast cancer; Non-small cell lung cancer; stabilized Nanoparticle Formulation) Pancreatic cancer
  • Neosar (Cyclophosphamide) Acute lymphoblastic leukemia; Acute
  • myeloid leukemia Breast cancer; Chronic lymphocytic leukemia; Chronic myelogenous leukemia; Hodgkin lymphoma; Multiple myeloma; Mycosis fungoides;
  • Neuroblastoma Non-Hodgkin lymphoma; Ovarian cancer; Retinoblastoma
  • Nivolumab Melanoma Squamous non-small cell lung cancer
  • Nolvadex (Tamoxifen Citrate) Breast cancer
  • Non-small cell lung cancer Ovarian cancer
  • Paclitaxel Albumin-stabilized Nanoparticle Breast cancer Non-small lung cancer
  • Platinol (Cisplatin) Bladder cancer Cervical cancer; Malignant mesothelioma; Non-small cell lung cancer; Ovarian cancer; Squamous cell carcinoma of the head and neck; Testicular cancer
  • Platinal-AQ (Cisplatin) Bladder cancer; Cervical cancer; Malignant mesothelioma; Non-small cell lung cancer; Ovarian cancer; Squamous cell carcinoma of the head and neck; Testicular cancer
  • lymphocytic leukemia Hodgkin lymphoma; Multiple myeloma; Non-Hodgkin lymphoma; Prostate cancer; Thymoma and thymic carcinoma
  • Purinethol Acute lymphoblastic leukemia
  • Rheumatrex (Methotrexate) Acute lymphoblastic leukemia; Breast cancer;
  • Gestational trophoblastic disease Head and neck cancer; Lung cancer; Non-Hodgkin lymphoma; Osteosarcoma
  • Rubidomycin Daunorubicin Hydrochloride Acute lymphoblastic leukemia; Acute
  • Somatuline Depot (Lanreotide Acetate) Gastroenteropancreatic neuroendocrine
  • Sorafenib Tosylate Hepatocellular carcinoma; Renal cell
  • Sutent Gastronintestinal stromal tumor; Pancreatic cancer; Renal cell carcinoma
  • Tasigna Chronic myelogenous leukemia
  • Taxol (Paclitaxel) AIDS-related Kaposi sarcoma; Breast cancer;
  • Non-small cell lung cancer Ovarian cancer
  • Taxotere Docetaxel Breast cancer; Adenocarcinoma; Non-small cell lung cancer; Prostate cancer; Squamous cell carcinoma of the head and neck
  • Thiotepa Bladder cancer ; Breast cancer; Malignant pleural effusion, malignant pericardial effusion, and malignant peritoneal effusion; Ovarian cancer
  • Torisel (Temsirolimus) Renal cell carcinoma
  • TPF Squamous cell carcinoma of the head and neck; Gastric (stomach) cancer
  • Treanda Bendamustine Hydrochloride B-cell non-Hodgkin lymphoma; Chronic lymphocytic leukemia
  • Trisenox Arsenic Trioxide Acute promyelocytic leukemia
  • Velban (Vinblastine Sulfate) Breast cancer; Choriocarcinoma; Hodgkin lymphoma; Kaposi sarcoma; Mycosid fungoides; Non-Hodgkin lymphoma;
  • Velsar Vehicle Sulfate Breast cancer; Choriocarcinoma; Hodgkin lymphoma; Kaposi sarcoma; Mycosis fungoides; Non-Hodgkin lymphoma;
  • VePesid Small cell lung cancer
  • Vincasar PFS Vincristine Sulfate Acute leukemia; Hodgkin lymphoma;
  • Neuroblastoma Non-Hodgkin lymphoma; Rhabdomyosarcoma; Wilms tumor
  • Zydelig Chronic lymphocytic leukemia; Non-Hodgkin lymphoma (Follicula B-cell non Hodgkin lymphoma and Small lymphocytic
  • the chemotherapeutic agent is associated with a carrier protein.
  • the effective amount of the chemotherapeutic is about 100 mg/m 2 , about 105 mg/m 2 , about 110 mg/m 2 , about 115 mg/m 2 , about 120 mg/m 2 , about 125 mg/m 2 , about 130 mg/m 2 , about 135 mg/m 2 , about 140 mg/m 2 , about 145 mg/m 2 , about 150 mg/m 2 , about 155 mg/m 2 , about 160 mg/m 2 , about 165 mg/m 2 , about 170 mg/m 2 , about 175 mg/m 2 , about 180 mg/m 2 , about 185 mg/m 2 , about 190 mg/m 2 , about 195 mg/m 2 , or about 200 mg/m 2 of the chemotherapeutic agent.
  • the therapeutic agent i.e., chemotherapeutic
  • the nanoparticle may contain more than one different therapeutic agents, for example, two therapeutic agents, three therapeutic agents, four therapeutic agents, five therapeutic agents, or more.
  • a nanoparticle may contain the same or different therapeutic agents inside and outside the nanoparticle.
  • any antibody, aptamer, therapeutic agent, or any combination thereof is expressly excluded.
  • complexes as described herein can be designed to have an average diameter that is less than 1 ⁇ .
  • appropriate concentrations of carrier protein and antibody (or other binding agent) can be used such that complexes having an average diameter that is less than 1 ⁇ are formed.
  • the complexes provided herein can have an average diameter that is between 0.1 ⁇ and 1 ⁇ (e.g., between 0.1 ⁇ and 0.95 ⁇ , between 0.1 ⁇ and 0.9 ⁇ , between 0.1 ⁇ and 0.8 ⁇ , between 0.1 ⁇ and 0.7 ⁇ , between 0.1 ⁇ and 0.6 ⁇ , between 0.1 ⁇ and 0.5 ⁇ , between 0.1 ⁇ and 0.4 ⁇ , between 0.1 ⁇ and 0.3 ⁇ , between 0.1 ⁇ and 0.2 ⁇ , between 0.2 ⁇ and 1 ⁇ , between 0.3 ⁇ and 1 ⁇ , between 0.4 ⁇ and 1 ⁇ , between 0.5 ⁇ and 1 ⁇ , between 0.2 ⁇ and 0.6 ⁇ , between 0.3 ⁇ and 0.6 ⁇ , between 0.2 ⁇ and 0.5 ⁇ m, or between 0.3 ⁇ and 0.5 ⁇ ).
  • Complexes provided herein having an average diameter that is between 0.1 ⁇ and 0.9 ⁇ can be administered systemically (e.g., intravenously)
  • a complex as provided herein can have greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes having a diameter that is between 0.1 ⁇ and 0.9 ⁇ (e.g., between 0.1 ⁇ and 0.95 ⁇ , between 0.1 ⁇ and 0.9 ⁇ , between 0.1 ⁇ and 0.8 ⁇ , between 0.1 ⁇ and 0.7 ⁇ , between 0.1 ⁇ and 0.6 ⁇ , between 0.1 ⁇ and 0.5 ⁇ , between 0.1 ⁇ and 0.4 ⁇ , between 0.1 ⁇ and 0.3 ⁇ , between 0.1 ⁇ and 0.2 ⁇ , between 0.2 ⁇ and 1 ⁇ , between 0.3 ⁇ and 1 ⁇ , between 0.4 ⁇ and 1 ⁇ , between 0.5 ⁇ and 1 ⁇ m, between 0.2 ⁇ and 0.6 ⁇ m, between 0.3 ⁇ and 0.6 ⁇ , between 0.2 ⁇ m and 0.5 ⁇ , or between 0.3 ⁇ and and
  • Complexes provided herein having greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes with a diameter that is between 0.1 ⁇ and 0.9 ⁇ can be administered systemically (e.g., intravenously) to treat cancer or other disease expressing the relevant antigen located within a mammal's body.
  • any appropriate combination of carrier protein, chemotherapy agent, and binding agent can be used as described herein.
  • an appropriate amount of carrier protein e.g., with a chemotherapeutic
  • an appropriate amount of binding agent can be mixed together in the same container.
  • This mixture can be incubated at an appropriate temperature (e.g., room temperature, between 5 °C and 60 °C, between 23 °C and 60 °C, between 15 °C and 30 °C, between 15 °C and 25 °C, between 20 °C and 30 °C, or between 20 °C and 25 °C) for a period of time (e.g., about 30 minutes, or between about 5 minutes and about 60 minutes, between about 5 minutes and about 45 minutes, between about 15 minutes and about 60 minutes, between about 15 minutes and about 45 minutes, between about 20 minutes and about 400 minutes, or between about 25 minutes and about 35 minutes) before being administered to a patient having a cancer.
  • an appropriate temperature e.g., room temperature, between 5 °C and 60 °C, between 23 °C and 60 °C, between 15 °C and 30 °C, between 15 °C and 25 °C, between 20 °C and 30 °C, or between 20 °C and 25 °C
  • the antibody-carrier protein-chemotherapy agent complex is lyophilized. Where the complex is lyophilized, it is reconstituted in a pharmaceutically acceptable excipient prior to administration to the patient.
  • carrier protein nanoparticles comprising a chemotherapy agent can be contacted with a binding agent to form complexes that are stored prior to being administered to a patient.
  • a composition can be formed as described herein and stored for a period of time (e.g., days or weeks) prior to being administered to a patient.
  • any appropriate method can be used to obtain complexes as described herein. Any appropriate method can be used to administer a complex as provided herein to a mammal.
  • a composition containing carrier protein/binding agent/chemotherapeutic complexes can be administered via injection (e.g., subcutaneous injection, intramuscular injection, intravenous injection, or intrathecal injection).
  • the carrier protein is albumin, gelatin, elastin, gliadin, legumin, zein, a soy protein, a milk protein, an antibody -binding protein, or a whey protein.
  • the carrier protein is albumin.
  • the albumin is human serum albumin.
  • the albumin is recombinant albumin.
  • anti-fugetactic agent to the cells prior to administration is contemplated to aid in penetration of the "fugetactic wall" surrounding the tumor as a result of chemokine (e.g., CXCL12) over-expression by the tumor.
  • Anti- fugetactic agents are agents with the ability to attenuate or eliminate the fugetactic effect of fugetactic agents.
  • Suitable agents with anti-fugetactic effect include AMD3100 (mozobil/plerixafor), KRH-1636, T-20, T-22, T-140, TE-14011, T-14012, TN14003, TAK- 779, AK602, SCH-351125, Tannic acid, NSC 651016, thalidomide, GF 109230X.
  • the anti-fugetactic agent is AMD3100.
  • the anti-fugetactic agent may be any such agent known in the art. In one
  • the anti-fugetactic agent is an anti-fugetactic agent as described in U.S. Patent Application Publication No. 2008/0300165, which is hereby incorporated by reference in its entirety.
  • the anti-fugetactic agent is AMD3100
  • the anti-fugetactic agent is an antibody that interferes with binding of the chemokine to its receptor.
  • the anti-fugetactic agent is AMD3100.
  • Anti-fugetactic agents include any agents that specifically inhibit chemokine and/or chemokine receptor dimerization, thereby blocking the chemorepellent response to a fugetactic agent.
  • Certain chemokines, including IL-8 and CXCL12 can also serve as chemorepellents at high concentrations (e.g., above 100 nM) where much of the chemokine exists as a dimer. Dimerization of the chemokine elicits a differential response in cells, causing dimerization of chemokine receptors, an activity which is interpreted as a
  • Blocking the chemorepellent effect of high concentrations of a chemokine secreted by a tumor can be accomplished, for example, by anti-fugetactic agents that inhibit chemokine dimer formation or chemokine receptor dimer formation.
  • anti-fugetactic agents that inhibit chemokine dimer formation or chemokine receptor dimer formation.
  • antibodies that target and block chemokine receptor dimerization e.g., by interfering with the dimerization domains or ligand binding, can be anti-fugetactic agents.
  • Anti-fugetactic agents that act via other mechanisms of action, e.g., that reduce the amount of fugetactic cytokine secreted by the cells, inhibit dimerization, and/or inhibit binding of the chemokine to a target receptor, are also encompassed by the present invention. Where desired, this effect can be achieved without inhibiting the chemotactic action of the monomeric chemokine.
  • the anti-fugetactic agent is a CXCR4 antagonist, CXCR3 antagonist, CXCR4/CXCL12 antagonist or selective PKC inhibitor.
  • the CXCR4 antagonist can be but is not limited to AMD3100, KRH-1636, T-20, T- 22, T-140, TE-14011, T-14012, or TN14003, or an antibody that interferes with the dimerization of CXCR4.
  • the CXCR3 antagonist can be but is not limited to TAK-779, AK602, or SCH- 351125, or an antibody that interferes with the dimerization of CXCR3.
  • the CXCR4/ CXCL12 antagonist can be but is not limited to Tannic acid, NSC 651016, or an antibody that interferes with the dimerization of CXCR4 and/or CXCL12.
  • the selective PKC inhibitor can be but is not limited to thalidomide or GF 10923 OX.
  • the anti-fugetactic agent is AMD3100 (plerixafor).
  • AMD3100 is described in U.S. Patent No. 5,583, 131, which is incorporated by reference herein in its entirety.
  • the anti-fugetactic agent is coupled with a molecule that allows targeting of a tumor or cancer.
  • the anti-fugetactic agent is coupled with (e.g., bound to) an antibody specific for the tumor to be targeted.
  • the anti-fugetactic agent is coupled to the molecule that allows targeting of the tumor or cancer.
  • the anti-fugetactic agent is bound to the modified haNK-92 cells in vitro (prior to administration to a patient). See, e.g., PCT Pub. No. WO2017/049228, which is incorporated herein by reference in its entirety.
  • the anti-fugetactic agent e.g. AMD3100, is bound to the haNK cells via CXCL4 expressed on the cell surface.
  • Cancers or tumors that can be treated by the compositions and methods described herein include, but are not limited to cancers listed in the above tables and: biliary tract cancer; brain cancer, including glioblastomas and medulloblastomas; breast cancer; uterine cancer; tubal cancer; cervical cancer; choriocarcinoma; colon cancer; bladder cancer; endometrial cancer; vaginal cancer; vulvar cancer; esophageal cancer; mouth cancer; gastric cancer; kidney cancer; hematological neoplasms, including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms, including Bowen's disease and Paget's disease; liver cancer (hepatocarcinoma); lung cancer; head or neck cancers or oral cancers (mouth, throat, esophageal, nasopharyngeal, jaw
  • neuroblastomas neuroendocrine tumors; oral cancer, including squamous cell carcinoma; adrenal cancer; anal cancer; angiosarcoma; appendix cancer; bile duct cancer; bone cancer; carcinoid tumors; soft tissue sarcoma; rhabdomyosarcoma; eye cancer; ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells, and fallopian tube cancer; gallbladder cancer; pancreas cancer; prostate cancer; rectal cancer; sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma; skin cancer, including melanoma, Kaposi's sarcoma, basocellular cancer and squamous cell cancer; testicular cancer, including germinal tumors (seminoma, non- seminoma[teratomas, choriocarcino

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Abstract

L'invention concerne des compositions destinées à améliorer le traitement du cancer par la combinaison, in vitro, de cellules NK-92 exprimant une fraction de liaison d'anticorps à haute affinité sur la surface cellulaire avec un anticorps qui reconnaît un épitope tumoral, de telle sorte que la fraction est liée à l'anticorps avant l'administration à un patient. Facultativement, de telles cellules NK-92 modifiées sont également liées à un agent anti-fugetactique. L'invention concerne également des procédés de fabrication et d'utilisation de ces dernières. L'invention concerne en outre des méthodes de traitement du cancer par co-administration des cellules NK-92 modifiées avec un complexe de chimiothérapie anticorps-albumine.
PCT/US2017/028016 2016-04-18 2017-04-17 Procédés et compositions destinés à améliorer la sécurité et l'efficacité d'une immunothérapie par cellules tueuses naturelles Ceased WO2017184534A1 (fr)

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US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
CN114269377A (zh) * 2019-07-26 2022-04-01 南克维斯特公司 作为用于肿瘤溶解的有效治疗性产品的抗体预加载cd16+nk-92细胞

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US5614373A (en) * 1992-09-17 1997-03-25 Merck Patent Gesellschaft Mit Beschrankter Haftung Tumor-specific antibodies and antigen
US20160067356A1 (en) * 2004-07-10 2016-03-10 Fox Chase Cancer Center Genetically modified human natural killer cell lines
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
CN114269377A (zh) * 2019-07-26 2022-04-01 南克维斯特公司 作为用于肿瘤溶解的有效治疗性产品的抗体预加载cd16+nk-92细胞
JP2022542368A (ja) * 2019-07-26 2022-10-03 ナントクウェスト，インコーポレーテッド 腫瘍溶解のための有効な治療用製剤としての、抗体を予め負荷したｃｄ１６＋ｎｋ－９２細胞
EP4003376A4 (fr) * 2019-07-26 2023-09-06 Nantkwest, Inc. Cellules cd16+nk-92 pré-chargées d'anticorps en tant que produit thérapeutique efficace pour la lyse tumorale
AU2020320187B2 (en) * 2019-07-26 2024-04-18 Immunitybio, Inc. Antibody pre-loaded CD16+NK-92 cells as an effective therapeutic product for tumor lysis
JP7555392B2 (ja) 2019-07-26 2024-09-24 ナントクウェスト，インコーポレーテッド 腫瘍溶解のための有効な治療用製剤としての、抗体を予め負荷したｃｄ１６＋ｎｋ－９２細胞
JP2024170601A (ja) * 2019-07-26 2024-12-10 ナントクウェスト，インコーポレーテッド 腫瘍溶解のための有効な治療用製剤としての、抗体を予め負荷したｃｄ１６＋ｎｋ－９２細胞

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