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WO2024233781A1 - Dispositifs pour améliorer l'activité d'anticorps thérapeutiques - Google Patents

Dispositifs pour améliorer l'activité d'anticorps thérapeutiques Download PDF

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Publication number
WO2024233781A1
WO2024233781A1 PCT/US2024/028579 US2024028579W WO2024233781A1 WO 2024233781 A1 WO2024233781 A1 WO 2024233781A1 US 2024028579 W US2024028579 W US 2024028579W WO 2024233781 A1 WO2024233781 A1 WO 2024233781A1
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Prior art keywords
therapeutic antibody
antigen
drug
antibody
subject
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James Joyce
Annette Marleau
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Sigyn Therapeutics Inc
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Sigyn Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
    • A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/342—Adding solutions to the blood, e.g. substitution solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3681—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3687—Chemical treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Therapeutic antibodies have provided novel and revolutionary treatment options for incurable diseases. Despite the great promise of antibody-based therapies, many antibodies have limited therapeutic activity and only marginal benefits in disease burden and survival for patients can be achieved. Several anatomical and physiological barriers impede the delivery and activity of therapeutic antibodies in target tissues. The amount of a therapeutic antibody that reaches its target site such as a tumor is estimated to be extremely low, which amounts to less than 2% of an administered dose or even lower according to certain estimates. Evidence has emerged that a fraction of a therapeutic antibody dose is intercepted by soluble factors in circulation that express antigens derived from diseased cells or disease-affected cells, allowing these circulating factors to act as decoys of a therapeutic antibody.
  • exosomes small extracellular vesicles, termed "exosomes" are abundant in the bloodstream of patients with various diseases and conditions. Exosomes derive from diseased, infected, or immune-modified cells and carry a plethora of surface-expressed proteins and molecules having the same membrane topology as targets of therapeutic antibodies. High levels of these circulating decoys are associated with poor therapeutic outcomes in numerous diseases including cancer and represent an unaddressed limitation of antibody therapy.
  • Immune checkpoints may be described as an array of stimulatory and inhibitory pathways that fine-tune immune responses and include molecules such as programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4) and others that have gained attention as immunotherapy targets.
  • Immune checkpoint inhibitors a class of monoclonal antibodies and related drugs, have achieved success in oncology practice for treating diverse tumor types.
  • the efficacy of immune checkpoint inhibitors is limited for some patients and certain tumor types and resistance often develops after an initial clinical response. Across various tumor types, only approximately 20-30% of patients have durable clinical benefits from immune checkpoint inhibitors. Improved or combination therapies are sought for improving patient responsiveness to these drugs.
  • Soluble factors in the bloodstream have been implicated in resistance to immune checkpoint inhibitors as well as to other antibody-based drug therapies used for treating cancer and a plethora of other conditions.
  • the mechanisms of action of soluble factors involves binding and sequestering therapeutic antibody drugs that are directed against these same antigens in a target tissue.
  • Soluble factors are therefore a reservoir of antigen that impede the delivery of therapeutic antibody drugs to their intended target antigens.
  • studies have demonstrated the presence of soluble forms of PD-L1 that bind to and sequester administered anti-PD-Ll therapeutic antibodies drugs in the bloodstream of subjects undergoing treatment for cancer.
  • trastuzumab (Herceptin®), an anti-HER2 (human epidermal growth factor receptor 2) monoclonal antibody approved for HER2-positive tumor types was bound to soluble HER2 antigen in patients' serum following intravenous infusion of the drug (Battke et al. Cancer Immunol Immunother 2011; 60: 639-648).
  • the present invention provides devices, kits, and methods for improving the delivery and activity of therapeutic antibody drugs by clearing or removing soluble factors that have drug antagonistic activities from the circulatory system of a subject.
  • the invention provides extracorporeal therapies that can be deployed as part of a regimen with therapeutic antibody drug administration into a patient.
  • the invention provides a dual mode of therapeutic antibody exposure, wherein blood or plasma is contacted with a first therapeutic antibody in an extracorporeal device prior to or following administration of a pharmaceutical composition of a second therapeutic antibody drug to the subject for treatment of a disease, or vice versa.
  • the invention is useful for enhancing the activity of antibody drugs that are administered to a subject to target cell membrane proteins, circulating proteins, and signaling pathways within cells.
  • the invention addresses the soluble factors in circulation that bind to and sequester therapeutic antibody drugs that are administered for treatment of a disease.
  • the soluble factors that are targets of the devices disclosed herein comprise antigens that are cleaved, secreted, or shed by cells, often by diseased cells, infected cells, tissue-specific cells, or other cells affected by a disease or that are produced in response to treatment of a disease.
  • a soluble factor comprises an antigen that is the same as the intended target antigen of a therapeutic antibody drug and thereby molecularly impedes the activity or distribution of the therapeutic antibody drug upon administration of said drug to a subject.
  • a soluble factor may comprise one or more of the following types of molecules: an antibody, a tumor-associated antigen, a tissue-specific antigen, an angiogenesis-related protein, an immune checkpoint protein, a viral glycoprotein, a pathogen- derived protein, a bacterial toxin, a complement component, an integrin, a cytokine, a cytokine receptor, a chemokine, a chemokine receptor, a lymphocyte receptor, a lymphocyte-expressed ligand, a B-cell receptor component, a transmembrane glycoprotein, a cell adhesion molecule, a ganglioside, a receptor tyrosine kinase, a fibroblast growth factor, a transforming growth factor superfamily protein, a microtubule-associated protein, a serine protease, or a
  • Embodiments of the invention provide extracorporeal devices that employ an affinity capture mechanism to bind one or a plurality of soluble factors present in blood or a plasma, wherein the one or a plurality of soluble factors are retained in the device and removed from the blood or plasma.
  • a soluble factorthat is bound and removed from blood or plasma using an extracorporeal device disclosed herein comprises an antigen that is non-cell- associated or free in circulation.
  • a soluble factor that is bound and removed from blood or plasma using a device disclosed herein comprises an antigen that is a component of a multi-antigen entity such as a vesicle or a particle.
  • an extracorporeal device is configured to bind to an entity in blood or plasma comprising the soluble antigen, wherein the entity comprises one or more of the following: a microparticle, an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular a nanoparticle (e.g., an exomere or a supermere), an apoptotic body, a protein, a glycoprotein, a glycolipid, or an anti-drug antibody.
  • a soluble factor that is the target of the extracorporeal devices disclosed herein may be present in one or more of the abovementioned forms due to the multiple mechanisms that are employed by the originating cell to expel its molecular cargo into the bloodstream.
  • a soluble factor is present in a subject with a tumor.
  • a soluble factor comprises one or more of the following antigens: Programmed death -ligand 1 (PD-L1), Programmed cell death protein 1 (PD-1), Cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), CD137, CD20, HER2, Tumor-associated calcium signal transducer 2 (TROP-2), CD37, CD38, disialoganglioside GD2, Epithelial cell adhesion molecule (EPCAM), CD30, CD33, CD22, CD19, CD79b, B Cell Maturation Antigen (BCMA), CD123 (alpha chain of IL-3 receptor), B7-H3 (CD276), Nectin Cell Adhesion Molecule 4 (Nectin-4), CD73 (ecto- 5'-nucleotidase), CD39, Immunoglobulin-like transcript 2 (ILT2), Immunoglobulin-like transcript 2 (ILT2), Immunoglobulin
  • an extracorporeal device comprises a cartridge, wherein the cartridge comprises a substrate to which a therapeutic antibody is immobilized to bind at least one soluble factor from blood or plasma and retain the soluble factor within the cartridge.
  • a ligand comprises a therapeutic antibody or an antigen-binding fragment thereof.
  • an extracorporeal device is a cartridge that coupled to an industry-standard apheresis machine, wherein whole blood is extracted from a subject, the plasma component is separated and subsequently treated by passage through the cartridge to remove one or a plurality of soluble factors. The processed plasma is then reintroduced with the non-treated blood components and reintroduced into the bloodstream of the subject.
  • an extracorporeal procedure is performed prior to infusion of a therapeutic antibody drug into a subject for treatment of a disease or condition.
  • the devices and methods disclosed herein incorporate a therapeutic antibody into an extracorporeal device to clear or remove a soluble factor that arises or increases in blood following infusion of a therapeutic antibody drug into a subject.
  • Certain embodiments provide devices and methods for the removal of an anti-drug antibody.
  • Other embodiments provide devices and methods for the removal of a soluble factor that comprises a disease-related or disease-associated antigen that is induced by administration of a therapeutic antibody drug to a subject, wherein the level of the disease-related or disease-associated antigen is increased in blood or plasma following therapeutic antibody drug administration.
  • a subject in need of treatment with a drug formulation of a first therapeutic antibody to target an antigen in a tissue is also provided with at least one treatment with an extracorporeal device comprising a second therapeutic antibody to target a soluble form of the antigen in blood or plasma.
  • the first therapeutic antibody in the drug formulation and the second therapeutic antibody in the extracorporeal device have binding specificity for the same antigen.
  • the first therapeutic antibody in the drug formulation and the second therapeutic antibody in the extracorporeal device bind to the same epitope of an antigen.
  • the first therapeutic antibody and the second therapeutic antibody are the identical, wherein the full- length antibodies and/or their antigen-binding portions or domains have identical amino acid sequences.
  • the first therapeutic antibody and the second therapeutic antibody comprise non-identical variants, wherein the full-length antibodies and/or their antigen-binding portions or domains have at least one conservative amino acid difference, and wherein a conservative amino acid difference reflects the presence of an amino acid having a biologically similar residue in comparison to another amino acid; i.e., a residue difference that does not confer a loss or gain of biological function of the antibody.
  • the first therapeutic antibody and the second therapeutic antibody are non-identical, wherein the first therapeutic antibody and the second therapeutic antibody may be configured to bind to a different epitope of an antigen or to different antigens on a molecule.
  • aspects of the invention provide extracorporeal devices comprising an immune checkpoint inhibitor antibody and methods of use for the purpose of clearing or reducing one or more soluble factors comprising immune checkpoint proteins from circulating blood.
  • the extracorporeal devices disclosed herein are useful for pre-clearance of soluble factors that act as drug antagonists, including soluble antigens, soluble splice variants of antigens, and antigens displayed by extracellular vesicles or exosomes or on microparticles, prior to administration of a pharmaceutical composition of a therapeutic antibody drug.
  • an extracorporeal device disclosed herein is utilized to clear or remove soluble immune checkpoint proteins that arise following infusion of one or more doses of a therapeutic antibody to a patient.
  • the methods described herein may be used to modify the pharmacokinetics and/or the pharmacodynamics of a therapeutic antibody drug such as an immune checkpoint inhibitor.
  • kits that is useful for practicing the treatment methods described herein.
  • a kit comprises components for delivering a therapeutic regimen of the invention to a subject.
  • a kit comprises at least one extracorporeal device described herein comprising a therapeutic antibody and at least one drug formulation comprising a therapeutic antibody.
  • kits that is useful for selecting a subject to receive treatment with an extracorporeal device of the invention.
  • a kit comprises materials for performing a biomarker assay to assess the presence and/or the concentration of at least one soluble factor in a blood or plasma of the subject.
  • the kit comprises at least one extracorporeal device described herein, which may be applied for removal of one or more soluble factors that have first identified and/or quantified in the biomarker assay.
  • Certain embodiments also provide one or more corresponding dose units of a therapeutic antibody drug in the kit.
  • kits for harvesting and assessing disease-related biomarkers from a subject undergoing treatment with a therapeutic regimen of the invention may be useful for assaying the soluble factors that were captured by an extracorporeal device during a subject's treatment session.
  • Certain embodiments provide a kit comprising materials and reagents for elution and analysis of bound materials from a used extracorporeal device that was retained after treatment of a subject.
  • a kit comprises an assay system for identifying or quantifying the recovered material, for example, an immunoassay, which may be used to assess the soluble factor(s) present in plasma or serum of the subject.
  • the methods comprise (a) identifying a subject in need of treatment with a drug formulation of a first therapeutic antibody, wherein the first therapeutic antibody drug is selected for its binding to an antigen, and wherein the antigen is present in the body as an antigen in a tissue target and as a soluble form of the antigen in blood or plasma; (b) introducing the blood or plasma from the subject into an extracorporeal device comprising a second therapeutic antibody, wherein the second therapeutic antibody is selected for its specificity for the soluble form of the antigen in blood or plasma, or portions thereof; (c) contacting the blood or plasma of the subject with the second therapeutic antibody in the extracorporeal device for a time sufficient to allow the soluble form of the antigen, or portions thereof to bind to the second therapeutic antibody; (d) reintroducing the blood or plasma obtained after (c) into the subject, wherein the blood or plasma obtained after (c) has a
  • Other embodiments provide methods for enhancing the efficacy of a therapeutic antibody drug by removing soluble factors from the bloodstream that arise following drug administration, for example, anti-drug antibodies or disease-related antigens carried on exosomes or other entities in blood or plasma.
  • the methods comprise (a) identifying a subject in need of treatment with a drug formulation of a first therapeutic antibody for treatment of a disease, wherein the first therapeutic antibody is selected for its binding specificity for an antigen, and wherein the antigen is present in the body as an antigen in a target tissue and as a soluble form of the antigen in blood or plasma; (b) administering the first therapeutic antibody to the subject, wherein a portion of the administered drug formulation of the first therapeutic antibody is bound to the antigen in the target tissue; (c) introducing the blood or plasma from the subject into an extracorporeal device comprising a second therapeutic antibody, wherein the second therapeutic antibody is selected for its binding specificity for the soluble form of the antigen in blood or plasma, or portions thereof; (d) contacting the blood or plasma from the subject with the second therapeutic antibody in the extracorporeal device for a time sufficient to allow the soluble form of the antigen, or portions thereof to bind to the therapeutic antibody; and (e) reintroducing the blood or plasma obtained after step (
  • Mainstream clinical practice aims to overcome the limitations of therapeutic antibody drugs using strategies such as delivering near-maximum tolerated doses for treating certain conditions or by providing combination therapies with other immunotherapies or cytotoxic drugs.
  • These treatment options have an increased likelihood of precipitating adverse events and leading to treatment discontinuation in a proportion of patients, as frequently seen in the oncology setting.
  • Other approaches have involved engineering the molecular architecture of antibodies into smaller or alternate formats however, this can impart loss of certain key effector functions via the antibody's constant (Fc) region, which include antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complementdependent cytotoxicity. It would therefore be advantageous to provide methods that improve the impact of a dose of therapeutic antibody drug against its intended target.
  • ADCC antibody-dependent cell cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • the present invention provides extracorporeal technologies for improving the pharmacokinetics and pharmacodynamics of therapeutic antibody drugs by binding and removing circulating drug inhibitors, termed "soluble factors" herein, that sequester or decoy these drugs.
  • Circulating drug inhibitors are present at the point of drug administration in large quantities, predominantly derived from diseased cells, immune cells, infected cells, and/or other cells that are affected by bystander disease processes.
  • Embodiments of the invention provide methods for reducing the circulating presence of drug antagonists that allow for increased effectiveness of a therapeutic antibody drug, as may be measured by established clinical efficacy endpoints that are standard for evaluating the drug and the disease indication.
  • Certain embodiments provide methods for improving drug delivery and for increasing the amount of a therapeutic antibody drug that reaches its intended target tissue, wherein the amount of the therapeutic antibody drug that is removed from the body by pharmacokinetic clearance mechanisms may be reduced and/or the amount of free therapeutic antibody drug (i.e., not bound to a soluble factor) is increased in blood or plasma and/or in another tissue such as a tumor, a lymph node, or an organ.
  • Yet other embodiments provide methods for lowering the required dose of a therapeutic antibody drug for administration to a subject for treatment of a disease by increasing the potency of a dose of drug or of a treatment regimen involving multiple doses. These embodiments may be performed to improve the efficacy and/or the safety of a therapeutic antibody drug that is administered to a subject.
  • the invention addresses the soluble factors in circulation that bind to and sequester therapeutic antibody drugs that are administered for treatment of a disease.
  • the soluble factors that are targets of the devices disclosed herein comprise antigens that are cleaved, secreted, or shed by cells, often by diseased cells, infected cells, tissue-specific cells, or other cells affected by a disease or that are produced in response to treatment of a disease.
  • a soluble factor comprises a soluble form of an antigen that is the same as the intended target antigen of a therapeutic antibody drug and thereby molecularly impedes the activity or distribution of the therapeutic antibody drug upon administration to a subject.
  • a soluble factor may comprise an antigen, wherein the antigen comprises one or more of the following types of molecules: an antibody, a tumor-associated antigen, a tissue-specific antigen, an angiogenesis-related protein, an immune checkpoint protein, a viral glycoprotein, a pathogen-derived protein, a bacterial toxin, a complement component, an integrin, a cytokine, a cytokine receptor, a chemokine, a chemokine receptor, a lymphocyte receptor, a lymphocyte-expressed ligand, a B-cell receptor component, a transmembrane glycoprotein, a cell adhesion molecule, a ganglioside, a receptor tyrosine kinase, a fibroblast growth factor, a transforming growth factor superfamily protein, a microtubule- associated protein, a se
  • the antigen comprises one or more of the following types of molecules: an antibody, a tumor-associated antigen, a tissue-specific antigen,
  • a soluble factor comprises one of the following antigens: Programmed death -ligand 1 (PD-L1), Programmed cell death protein 1 (PD-1), Cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), CD20, HER2, Tumor-associated calcium signal transducer 2 (TROP-2), CD37, CD38, disia loga nglioside GD2, Epithelial cell adhesion molecule (EPCAM), CD30, CD33, CD22, CD19, CD79b, B Cell Maturation Antigen (BCMA), CD123 (alpha chain of IL-3 receptor), B7-H3 (CD276), Nectin Cell Adhesion Molecule 4 (Nectin-4), CD73 (ecto- 5'-nucleotidase), CD39, Immunoglobulin-like transcript 2 (ILT2), Immunoglobulin-like transcript 4 (ILT4), tissue factor, folate receptor alpha (FRalpha), Carcinoembry
  • the soluble factors that are the targets of the disclosed devices and methods are produced in abundance by diseased cells and shed or secreted into the circulatory system as various molecularly distinct entities.
  • the invention advantageously provides methods for removing a soluble factor from the circulatory system that may exist as a component of one or more different molecular entities among the structurally diverse array of cell-derived secretory and shed molecules in plasma.
  • methods are provided to remove an entity from blood or plasma comprising a soluble antigen, wherein the entity comprises one or more of the following: a microparticle, an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular nanoparticle (e.g., an exomere, a supermere), an apoptotic body, a protein, a glycoprotein, a glycolipid, and/or an anti-drug antibody.
  • the technologies described herein are suitable for the simultaneous clearance of molecularly and biologically distinct entities from blood or plasma that comprise a common antigen.
  • a soluble factor comprises an antigen (also referred to herein as a "soluble antigen” or a "soluble form of an antigen”) that binds to a therapeutic antibody drug.
  • a soluble factor is carried on or displayed by an exosome or by another entity present in plasma.
  • exosomes in plasma of a subject may be present at concentrations of at least IO 10 vesicles/mL, at least 10 11 vesicles/mL, at least 10 12 /vesicles/mL, or higher.
  • exosomes in plasma may be present at less than 10 9 vesicles/mL, less than 10 8 vesicles/mL, less than 10 7 /vesicles/mL, or lower. Exosomes are released in particularly large quantities by diseased cells and comprise antigenic cargo that mirrors that of their cells of origin, therefore, the exosome content in plasma may be enriched for disease-related antigens.
  • exosomes carry antigens that are also the targets of therapeutic antibody drug formulations that are in clinical use, wherein the therapeutic antibody drug formulations are directed against an antigen in a target tissue, e.g., a tumor, a lymph node, blood, or another organ, but wherein exosomes act as "decoys" that compete for binding to the therapeutic antibody drug.
  • a target tissue e.g., a tumor, a lymph node, blood, or another organ
  • exosomes act as "decoys” that compete for binding to the therapeutic antibody drug.
  • the concentration of exosomes in plasma of a subject that carries or displays an antigen may be at least 10 6 vesicles/mL, at least 10 7 vesicles/mL, at least 10 8 /vesicles/mL, or higher.
  • the amount of an antigen carried or displayed by exosomes in plasma is capable of binding at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50% or more of a dose unit of an administered therapeutic antibody drug.
  • Embodiments of the invention therefore provide devices and methods to remove the soluble antigen component of plasma that substantially interferes with the interactions of a therapeutic antibody drug with its intended target antigen.
  • the uptake and sequestration of therapeutic antibodies by soluble factors in circulation is believed to have far-reaching implications in the landscape of therapeutic antibody drugs, wherein the target antigens of approved and investigational therapeutic antibody drugs are vulnerable to the decoying mechanism of action of extracellularvesicles. Soluble factors comprising disease-related antigens are therefore ubiquitous entities in subjects being treated with therapeutic antibody drugs.
  • Embodiments of the invention provide an extracorporeal device comprising a therapeutic antibody as an affinity capture ligand for removing soluble factors from the complex and concentrated plasma protein composition of blood.
  • the devices and methods of the invention thereby provide a novel mechanism of exposure to a therapeutic antibody, wherein the bloodstream is exposed to the therapeutic antibody extracorporeally.
  • the present invention provides extracorporeal devices that exhibit complementary mechanisms of action to therapeutic antibody drugs, wherein each treatment modality is provided to target a distinct portion or reservoir of the same antigen.
  • improved methods for treating a subject with a therapeutic antibody drug are provided, wherein a subject in need of treatment with a drug formulation comprising a first therapeutic antibody to target an antigen in a tissue is provided with at least one treatment with an extracorporeal device comprising a second therapeutic antibody to eliminate or reduce the soluble form of the antigen in blood or plasma of the subject.
  • the first therapeutic antibody in the drug formulation and the second therapeutic antibody in the extracorporeal device have binding specificity for the same antigen.
  • a first therapeutic antibody in the drug formulation and the second therapeutic antibody in the extracorporeal device bind to the same epitope of the antigen.
  • the first therapeutic antibody and the second therapeutic antibody are the same, wherein the full-length antibodies and/or their antigen-binding portions or domains have identical amino acid sequences.
  • the first therapeutic antibody and the second therapeutic antibody are non-identical and may comprise variants of each other, wherein the full-length antibodies and/or their antigen-binding portions or domains have at least one conservative amino acid difference, and wherein a conservative amino acid difference reflects the presence of an amino acid having a biologically similar residue in comparison to another amino acid; i.e., a residue difference that does not confer a loss or gain of biological function of the antibody, for example, in binding to an epitope.
  • a first therapeutic antibody and a second therapeutic antibody are non-identical, wherein the first therapeutic antibody and the second therapeutic antibody are configured to bind to a different epitope of an antigen.
  • the devices and methods disclosed herein may be desirable interventions for broad therapeutic areas where activation of the immune system is desired.
  • the devices and methods disclosed herein are useful for regulation or suppression of an immune or inflammatory response.
  • the disclosed systems and methods are useful for the treatment of cancer, infectious diseases, autoimmune disorders, metabolic disorders, neurodegenerative diseases, sepsis, graft-versus-host-disease, inflammatory reactions, and others.
  • the devices and methods of the invention may be applicable to a spectrum of diseases and conditions for which therapeutic antibody drugs are in use or in clinical development.
  • the terms "subject” refers to a human or a non-human mammal, for example, a dog or a cat, and may refer to a patient having a disease or condition.
  • treatment As used herein, the terms “treatment”, “therapy”, or “therapeutic” are used according to what is understood in the art as means for obtaining beneficial results in a subject's condition, for example, in the amelioration or lessening of a disease or symptom. Treatment may include administering a therapeutically effective amount of a drug or any active agent to a subject, or the application of an extracorporeal device disclosed herein as a form of therapy. In certain embodiments, the term “treating” refers to an intervention directed toward slowing, interrupting, reducing, or reversing the progression or severity of a disease, condition, or symptom.
  • the administering step of a treatment may consist of a single administration (e.g., of a therapeutic antibody drug) or a series of administrations at a dose, duration, and interval required to treat the subject, i.e., a treatment regimen.
  • a therapeutic antibody drug may be administered to a subject at a defined dose (e.g., defined as mg/m 2 or mg/kg) once per week, once every 2 weeks, once every 3 weeks, once every 4 weeks, or at another interval that is appropriate for treating the specific disease.
  • extracorporeal procedure or “extracorporeal treatment” refer to a treatment session with a device disclosed herein, wherein a subject's blood is withdrawn from the body, to remove disease-mediating and/or pathogenic substances from blood, and the filtered or treated blood is returned to the body.
  • the terms “cartridge” or “column” refer to a device which passes a body fluid, such as blood or plasma, from a subject, wherein the device comprises a material that interacts with the body fluid.
  • a device may contain one or more substrates or ligands comprising therapeutic antibodies that interact with the body fluid.
  • substrate refers to a capture support material such as a membrane, a fiber, a particle, or any other appropriate surface that provides a structure and a surface area, and that contains appropriate surface properties either for direct coupling of an affinity ligand or for coupling after modification or for surface derivatization/modification.
  • a substrate may comprise a porous or non-porous matrix material that is suitable to present a ligand.
  • a substrate may also refer to a bead, resin, affinity chromatography support material, hollow fiber membrane, sheet membrane, membrane cassette, rolled sheet membrane, and/or other materials.
  • a substrate may comprise one or more of the following materials: agarose, Sepharose®, cellulose, xylan, dextran, pullulan, starch, pore glass, silica, acrylamide and/or its derivatives, polyacrylamide beads, trisacryl, sephacryl, ultrogel AcA, azlactone beads, methacrylate derivatives, TSK-Gel Toyopearl* HW, HEMA, Eupergit ', PorosTM, polystyrene and/or its derivatives, or combinations thereof.
  • ligand refers to a material that possesses an affinity to bind to a target component or a target antigen.
  • a ligand comprises a binding site that will substantially bind to specific sites on a target antigen.
  • a ligand is a therapeutic antibody or a portion thereof.
  • a therapeutic antibody is non-detachably bound or immobilized to a substrate, which is intended to retain the therapeutic antibody and the complexed target antigen-therapeutic antibody on the substrate during an extracorporeal procedure.
  • a ligand may also comprise a linker, which refers to a compound or structure that couples two different structures (e.g., a ligand to a substrate).
  • a linker comprises one or more carbons.
  • a linker comprises a peptide linker, e.g., comprising Glycine (G) and/or Serine (S) amino acids of varying length (e.g., 1-20 units).
  • bead refers to a particle having a geometric shape or structure that may serve as a substrate or a component thereof.
  • An exemplary bead may have a solid form and a simple geometric form, for example a sphere or a rod, or a more complex form.
  • a bead may comprise one or more materials that confer a porous or non-porous overall structure including but not limited to agarose, SepharoseTM, xylan, dextran, pullulan, starch, the like or a combination thereof, each having a characteristic average or absolute diameter.
  • a bead may serve as an attachment surface for a ligand such as a therapeutic antibody.
  • an "antigen” refers to a protein, polysaccharide, glycoprotein, glycolipid, ora molecule that may be capable of reacting with an antibody molecule or an antigen receptor on a lymphocyte.
  • An antigen may have one or a plurality of epitopes that dictate the interactions with an antibody and the generation of an immune response, if applicable.
  • a disease-related antigen may include any antigen involved in a disease process or symptoms thereof.
  • a disease- related antigen is an antigen that is targeted by a therapeutic intervention, such as using a therapeutic antibody drug.
  • a disease-related antigen in the context of cancer may comprise a tumor-specific antigen or a tumor-associated antigen, including but not limited to oncofetal, oncoviral, lineage-restricted, mutated, post-translationally altered, idiotypic, or overexpressed antigens including receptors and ligands that are also expressed by healthy cells or tissues.
  • a disease-related antigen may also refer to a molecule with immune suppressive functions (e.g., an immune checkpoint protein).
  • a disease-related antigen may be present in a target tissue.
  • a disease-related antigen may be present in blood or plasma in a soluble form: i.e., as a soluble factor/soluble antigen.
  • the term "epitope" refers to an antigenic determinant, or a site of an antigen to which a therapeutic antibody exhibits binding specificity.
  • An epitope comprises sequential amino acids of an antigen which, typically are 5-8 amino acids in length but can be shorter or longer.
  • an epitope may refer to a site on an immunogenic antibody to which another antibody binds.
  • target refers to a chemical, compound and/or an organic structure with which a ligand such as a therapeutic antibody is intended to interact.
  • a target may be an organic structure, for example a receptor or a ligand, for which a therapeutic antibody has binding specificity.
  • target tissue refers to group of cells organized in relative proximity that have various degrees of structural and functional similarity (e.g., a tumor, a lymph node, blood, or an organ) that a therapeutic antibody is intended to localize to and/or interact with.
  • a “target tissue” may refer to a site comprising an antigen for which a therapeutic antibody has binding specificity.
  • target antigen refers to an antigen that comprises an intended binding site, region or epitope for which a therapeutic antibody exhibits binding specificity.
  • soluble factor As used herein, the terms “soluble factor”, “soluble form of an antigen”, or “soluble antigen” may be used interchangeably to refer to an antigen derived from a cell or a cell membrane by cleavage, secretion, shedding, cell disassembly, apoptosis, membrane, or other mechanisms, and can be detected and quantified in the circulatory system.
  • a soluble factor may comprise an antigen or a molecule that binds, sequesters, or otherwise physically or molecularly impedes the activity or distribution of a therapeutic antibody that is administered to a subject.
  • a "soluble antigen” refers to a soluble form of an antigen in blood or plasma that is the same as the intended target antigen of a therapeutic antibody drug.
  • the term "identical” may be used to describe two or more referenced entities (e.g., therapeutic antibodies or antigens) that are the same when their amino acid sequences are aligned.
  • the sequences of two or more referenced entities may be identical over a defined region or domain of a molecule or over a full-length molecule.
  • the alignment of contiguous amino acids for two or more molecules and the determination of the extent of identity can be determined using computer programs and algorithms that are known in the art.
  • the term "therapeutic antibody” broadly refers to an immunoglobulin that is selected for therapeutic use based on its binding specificity for an antigen and its affinity for the antigen, wherein an antigen may comprise a soluble factor or an antigen in a tissue such as a pathogen, a cell surface antigen, a plasma protein, an antibody, or another molecule.
  • a therapeutic antibody may be various isotypes including human IgGl, lgG2, lgG3 or lgG4.
  • a "full-size” or “full-length” antibody is composed of two identical heavy chains and two identical light chains assembled into three discrete functional domains.
  • a full-size therapeutic antibody typically has a molecular weight of approximately 150 kDa.
  • Two antigen-binding fragments (Fabs) are responsible for binding to a specific molecular target with high avidity.
  • the crystallizable fragment (Fc) binds to immune receptors to elicit effector functions.
  • the N-terminal half of the Fab arms contains the variable sequences, which differ between antibodies to confer distinct specificities.
  • Three complementarity-determining regions (CDRs) on each chain contain hypervariable sequences that are situated at the antigen-binding interface. The remainder of the amino acid sequence contains constant regions that are identical for antibodies of a given subclass.
  • therapeutic antibody may also refer to a portion, domain, or region of an antibody or an engineered antibody or an antibody-like molecule.
  • a therapeutic antibody may comprise an antibody molecule that retains an antigen-binding region but lacks one or more regions or domains of a full-size antibody.
  • therapeutic antibody may refer to a molecule has at least one CDR of an antibody, wherein a CDR delineates specific regions within the variable region in each light and heavy chain that forms the antigen-binding site of an antibody, or the regions of an antibody that are complementary to the structure of an epitope.
  • a therapeutic antibody possesses characteristic properties of recognizing and binding to at least one molecule or antigen, and to at least one epitope of an antigen.
  • an antigen-binding portion, region, or domain of a therapeutic antibody may comprise a single chain variable fragment (scFv), which is the smallest unit of an immunoglobulin molecule that can function in antigen binding.
  • the scFv antibody consists of variable regions of heavy (VH) and light (VL) chains, joined together by a flexible peptide linker and having a molecular weight of approximately 25 kDa, which is much smaller than that of a full-length mAb.
  • An antigen-binding portion or region of a therapeutic antibody may comprise an antigen-binding fragment (Fab) or an F(ab')z.
  • a conventional Fab comprises a monovalent fragment consisting of one light chain and one heavy chain linked by a disulfide bond with a molecular weight of approximately 55 kDa
  • non-limiting examples of commercial Fab therapeutic antibodies include abciximab (Reopro®), idarucizumab (Praxbind®), and ranibizumab (Lucentis®).
  • An F(a b'Jz may comprise a bivalent fragment composed of two Fab segments linked together by a hinge region with a molecular weight of approximately 110 kDa.
  • An antigen-binding portion of a therapeutic antibody may also comprise an antibody light chain ora fragment thereof, an antibody heavy chain ora fragment thereof, a light chain variable region or a fragment thereof, a heavy chain variable region or a fragment thereof, one or more CDRs, or a combination or plurality thereof.
  • a therapeutic antibody may refer to a monoclonal antibody, a polyclonal antibody, a bispecific antibody, a chimeric antibody, a humanized antibody, a multivalent antibody and/or a multi-specific antibody.
  • a therapeutic antibody may comprise one or more of the following: miniaturized antibody, multi-functionalized antibody, antibody-drug conjugate (ADC), antibody-oligonucleotide conjugate, antibody-cytokine fusion protein, single domain antibody, diabody, triabody, minibody, tandem scFv, affibody, designed ankyrin repeat protein (DARPin), monobody, dual-variable-domain Ig, tetravalent IgG-like antibody, multispecific scFv, IgG-scFv fusion protein, multispecific Fab, tandem VHH domain, IgG-like constructs (with Fc region), non-IgG-like fragment (lacking an Fc region), DVD-lg dual-variable- domain immunoglobulin, bispecific T-cell engager (BiTE), HLE-BiTE half-life-extended BiTE (HLE- BiTE), tandem diabody (TandAb), DART (dual-affinity retargeting molecule), cross-over dual variable region
  • a therapeutic antibody may refer to a single-domain antibody or a portion thereof, wherein the antibody or portion thereof comprises a variable domain that is capable of specifically binding an antigen and/or an epitope of an antigen, in the absence of an additional antibody domain.
  • Single-domain antibodies may comprise VH domain antibodies, VNAR antibodies, camelid VHH antibodies, and VL domain antibodies, wherein VNAR antibodies may be produced by cartilaginous fish, wobbegong sharks, spiny dogfish, or bamboo sharks.
  • Camelid VHH antibodies may be produced by camel, llama, alpaca, dromedary, orguanaco, which produce heavy chain antibodies that are naturally devoid of light chains.
  • a therapeutic antibody may refer to an antibody that is incorporated into an extracorporeal device disclosed herein for treatment of a subject, wherein the subject's circulatory system is exposed to the therapeutic antibody outside the body.
  • the invention also references therapeutic antibodies that are administered to a subject as a means of treating a subject, for example, antibodies administered by injection or intravenous infusion to a site in the body.
  • a therapeutic antibody for administration to a subject is referred to as a "therapeutic antibody drug", also described herein as a "drug formulation” or a "pharmaceutical formulation”.
  • a pharmaceutical formulation of a therapeutic antibody may comprise a therapeutically effective amount of a therapeutic antibody in a pharmaceutically acceptable carrier and may further comprise one or more additional substances having a medicinal effect.
  • binding specificity may refer to the ability of an antibody to recognize and bind its intended antigen or epitope and/or the ability of an antibody to discriminate between similar antigens, as dictated by the antigen-binding portions, regions, or domains of the antibody
  • humanized antibody refers to an antibody that includes a human framework region and one or more CDRs from a non-human (for example a mouse, rabbit, rat, shark or synthetic) immunoglobulin.
  • a humanized antibody binds to the same antigen as the donor antibody that provides the CDRs.
  • Humanized or other monoclonal antibodies can have additional conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions.
  • affinity or "binding affinity” are defined as the strength of the binding interaction between two molecules, for example, between a receptor and a ligand or between the antibody and an antigen.
  • assessments are performed of the affinity of interactions of a therapeutic antibody with a soluble factor comprising an antigen.
  • affinity of a therapeutic antibody for a target molecule comprising an antigen is measured. Affinity is dependent on the stereochemical fit and the contact area between antibody sites and antigen determinants as well as the presence of charged and hydrophobic groups. Measurements of affinity of an antibody can be performed using methods known to one of ordinary skill in the art such as surface plasmon resonance (SPR), biolayer interferometry (BLI), and others.
  • SPR surface plasmon resonance
  • BBI biolayer interferometry
  • CDR complementarity determining region
  • framework region refers to amino acid sequences interposed between CDRs that include light and variable heavy framework regions.
  • the framework regions serve to hold the CDRs in an appropriate orientation for antigen binding.
  • the term "drug” refers to a pharmaceutical formulation or composition, which may comprise a chemical agent, a synthetic agent, natural/biological agent or a combination thereof, that is administered to a subject, specifically an agent that is administered directly to a site in the body.
  • a drug may comprise a therapeutic antibody and may further comprise an acceptable carrier, diluent and/or excipient. Preparation of a therapeutic antibody into a drug formulation can be performed using methods well known in the art.
  • a drug of the present invention may be administered to a subject in single or multiple doses.
  • Routes of administration of a therapeutic antibody drug may include intravenous subcutaneous, intraperitoneal, oral, sublingual, inhalation, topical application or cutaneous, subcutaneous, or intraarterial.
  • a drug may be administered locally rather than systemically, for example, via injection of the drug directly into a tissue, as a depot or sustained release formulation, or in a targeted drug delivery system.
  • therapeutic antibody drugs of the invention may refer to already developed and marketed drugs.
  • the term "therapeutically effective” refers to a quantity, dose, and/or duration of a therapeutic intervention, which may be a drug or a device, that will elicit the biological or medical response or desired therapeutic effect on a tissue, system, animal, mammal or human that is being sought by the researcher, medical doctor, or other clinician.
  • infusion refers to intravenous administration of a drug such as a therapeutic antibody.
  • a drug such as a therapeutic antibody.
  • infusion of a therapeutic antibody is a procedure that can vary in duration from approximately 15 min to 70 min, and often 30-60 min for some drugs.
  • post-infusion observation period 60 minutes or more duration which a patient is monitored for possible reactions to the drug.
  • the procedures for infusion can vary according to the subject, the therapeutic antibody, or the disease or condition that is being treated.
  • fragment or “portion” may refer to a shortened amino acid sequence of a molecule, an antigen, or an antibody from its full-length or native form that may arise either physiologically or by molecular manipulation or engineering.
  • immune checkpoint protein refers to a molecule that is involved in regulating immune cell activation, which may involve inhibitory or stimulatory signaling into cells.
  • An immune checkpoint protein may be a membrane-bound receptor or ligand, or it may comprise a soluble entity released by a cell into a body fluid such as blood or a blood component such as plasma.
  • microparticle refers to a cell product of heterogeneous size (micron, sub-micron, or nano-sized) that may be membranous or non-membranous, secreted, cleaved, or shed from a cell, and may include microvesicles (100-1000 nm in diameter), exosomes (30-150 nm), ectosomes (50-1000 nm), membrane particles (50-80 nm), exosome-like vesicles (20-50 nm) and apoptotic vesicles (50- 500 nm).
  • the major distinguishing parameter for these different types of microparticles is their size and/or their cellular origins.
  • a microparticle expresses an antigen on its surface that binds to a therapeutic antibody.
  • extracellular vesicle broadly defines a cell-derived vesicle that can be separated from non-membranous particles in blood or plasma.
  • Extracellular vesicles may range in size up to approximately 500 nm or 1,000 nm in diameter, and may include microvesicles, exosomes, and apoptotic bodies, or other vesicles that are secreted or pinched off the surfaces of parent cells.
  • an extracellular vesicle expresses an antigen on its surface that binds to a therapeutic antibody, or for which a therapeutic antibody has binding affinity.
  • exosome refers to a bi-lipid membrane vesicle of approximately 30-150 nm in diameter (a small type of EV) that is secreted by a cell.
  • exosomes may be found in higher concentrations in blood or plasma as compared to their concentrations in healthy individuals in the absence of a disease diagnosis or symptoms.
  • Exosomes may carry certain components from cell membranes including ligands and receptors.
  • an exosome expresses or displays an antigen or an epitope on its surface that binds to a therapeutic antibody.
  • Exosomes can be isolated from other plasma or serum components are identified or selected by surface proteins unique to the endosomal pathway, which can be used for identification and to distinguish them from other soluble factors, including tetraspanins such as CD9, CD63, CD81, heat shock proteins (e.g., HSP70), lysosomal proteins (e.g., Lamp2b), and the tumor-sensitive gene 101 (TsglOl), and fusion proteins (e.g., flotillin and annexin).
  • the concentrations of exosomes in plasma of a subject may exhibit a positive correlation with the presence of disease and/or the severity of a disease.
  • the concentrations of exosomes comprising a disease-related antigen in plasma of a subject may be positively correlated with the presence or stage of a disease.
  • microvesicle defines a vesicle ranging from 50 nm to 1000 nm in diameter, and generally includes vesicles that may be larger than exosomes, that derives from plasma membrane invaginations that capture cytoplasmic contents.
  • a microvesicle expresses an antigen on its surface that binds to a therapeutic antibody.
  • extracellular nanoparticle refers to a non-membranous particle released by a cell; for example, an exomere or a supermere.
  • an extracellular nanoparticle comprises an antigen that binds to a therapeutic antibody.
  • exomere refers to a small (approximately 30-50 nm) non-membranous extracellular nanoparticle.
  • supermere refers to a smaller ( ⁇ 30 nm) nanoparticle. Both exomeres and supermeres may be detected in the circulatory system and are replete in disease biomarkers and clinically relevant cargo.
  • apoptotic body refers to a soluble factor that is released during apoptosis of a cell.
  • An apoptotic body is essentially a remnant of a cell that may contain an assortment of cellular components including protein, lipids and/or genetic material.
  • apoptotic bodies may be present in blood or plasma in a subject, wherein the quantities of apoptotic bodies may exhibit a positive correlation with the presence of disease and/or the severity of a disease or condition.
  • an apoptotic body may be identified as heterogeneously shaped vesicles with sizes between 50-5000 nm and by high amounts of phosphatidylserine in their membrane, which may be discerned using methods known to one or ordinary skill in the art.
  • an apoptotic body comprises an antigen that is the target of the extracorporeal devices and methods disclosed herein.
  • anti-drug antibody refers to a drug-specific antibody that is elicited following administration of a therapeutic antibody to a subject.
  • Other terms that may be used in the art to describe an anti-drug antibody include "anti-therapeutic antibody”, “anti- product antibody”, or “anti-biologic antibody”.
  • Biologic agents, including therapeutic antibodies are known to have immunogenic potential, wherein immunogenic antibodies induce immune responses against the drug itself, leading to the formation of anti-drug antibodies.
  • anti-drug antibodies can trigger adverse events such as pharmacological abrogation of the drug or hypersensitivity reactions.
  • Anti-drug antibodies can be neutralizing or non-neutralizing.
  • Neutralization by an anti-drug antibody may occur when the anti-drug antibody binds to the CDR of the therapeutic antibody drug.
  • the effects may include preventing the therapeutic antibody drug from binding to its target antigen and the formation of immune complexes, which can lead to increased drug clearance.
  • Non-neutralizing anti-drug antibodies bind to non-selective epitopes of the therapeutic antibody, such as the Fc region, which may confer decreased therapeutic activity and/or may lead to increased clearance of the therapeutic antibody drug from the body.
  • Anti-drug antibodies therefore affect the total drug exposure and may affect a drug's safety and efficacy. The risk of compromised safety and efficacy of a therapeutic antibody drug is increased by the presence of high titers of high-affinity neutralizing anti-drug antibodies.
  • Anti-drug antibodies may cause serious side effects, including infusion reactions, cross-reactivity against endogenous proteins by neutralizing antibodies, and complement activation. Induction of anti-drug antibodies has been described for numerous therapeutic antibodies including but not limited to those used to treat rheumatoid arthritis (adalimumab and infliximab), Crohn's disease (infliximab), multiple sclerosis (natalizumab and alemtuzumab) and plaque psoriasis (adalimumab). Immunogenicity evaluations are commonly performed for the detection and characterization of anti-drug antibodies, the results of which provide information for patient safety and efficacy of a therapeutic antibody.
  • the present invention provides extracorporeal devices for the removal of drugbinding and drug-sequestering soluble factors from blood or plasma of a subject that act as decoys of therapeutic antibody drugs.
  • plasma comprises copious quantities of soluble factors, wherein a proportion of the soluble factors in plasma comprise one or more disease-related antigens that are the targets of pharmaceutical compositions of therapeutic antibody drugs used to treat the disease or medical condition, and wherein a proportion of the disease-related antigens bind to the therapeutic antibody drug, thereby sequestering or neutralizing the drug and lowering the effective dose .
  • the present invention provides a solution to this problem by disclosing devices for pre-clearance of soluble factors from the bloodstream that interfere with activity of a therapeutic antibody drug and that reduce the effective or active drug concentrations in the body. Additionally, the invention provides devices for removal of soluble factors that arise as biological or immunological responses to therapeutic antibody drug administration.
  • the devices disclosed herein can be utilized as part of a therapeutic regimen with pharmaceutical compositions of therapeutic antibody drugs known in the art. The implementation of an extracorporeal device of the invention is therefore tailored to the therapeutic antibody drug being administered to a subject and the soluble factor to be cleared.
  • the present disclosure provides extracorporeal devices comprising one or a plurality of therapeutic antibodies that are configured to reduce the concentrations of drug-binding factors from the bloodstream, which may be provided as an enhancement therapy to a pharmaceutical composition of a therapeutic antibody drug that is directed against the same antigen.
  • the devices disclosed herein can incorporate any therapeutic antibody drug including commercially available antibody drugs, or portions, domain, or variants thereof, including but not limited to monoclonal antibodies, bi-specific antibodies, multi-specific antibodies, engineered variants or fragments of antibody molecules, antibody mimetics, or other antibody formats.
  • Certain embodiments provide extracorporeal devices comprising a full-size therapeutic antibody with a molecular weight of approximately 150 kDa.
  • extracorporeal devices comprise alternate therapeutic antibody formats or fragment or domains thereof, for example, having molecular weights ranging from 5 kDa up to 150 kDa or larger if additional moieties are attached.
  • the present invention provides devices that facilitate direct exposure of the circulatory system to the therapeutic antibody outside of the body. Moreover, repeated passage or exposure of the blood or plasma through an extracorporeal device can be achieved in a single treatment session with the extracorporeal device.
  • An extracorporeal treatment approach circumvents the dosing limitations that exist for pharmaceutical formulations of therapeutic antibodies. For example, a primary mechanism underlying toxicity of therapeutic antibody drugs relates to exaggerated pharmacology related to blocking or enhancing the activities of the target antigen, which can lead to high levels of immunosuppression, immune activation, or highly skewed immune modulatory effects. For these reasons, drug concentrations that are lower than a therapeutically effective dose are often indicated.
  • Embodiments of the invention provide extracorporeal devices to enhance the performance of a therapeutic antibody drug against its intended target antigen, irrespective of the anatomic localization of the target antigen.
  • a therapeutic antibody drug is administered to a subject that has binding specificity for one or more antigens expressed in a target tissue such as a lymph node, a tumor, or an organ, or a combination thereof.
  • a target tissue such as a lymph node, a tumor, or an organ, or a combination thereof.
  • a monoclonal antibody has binding specificity for a single antigen while a bispecific antibody has binding specificity for two antigens.
  • an extracorporeal device for the purpose of eliminating or reducing drug antagonists from the bloodstream, thereby offering a means to improve the systemic availability of therapeutic antibody drug to be distributed to the target tissue.
  • a therapeutic antibody drug is administered to a subject that has binding specificity one or more antigens in the bloodstream, for example, a therapeutic antibody drug for treating a hematologic malignancy such as leukemia, lymphoma, or myeloma, wherein an antigen is expressed on a blood cell.
  • an extracorporeal device is provided to remove one or more soluble antigens that compete with the intended target antigen for binding to the therapeutic antibody drug in the bloodstream.
  • the systems for delivering extracorporeal therapy are configured to separate plasma from whole blood, wherein the plasma component is subsequently subjected to an affinity capture mechanism for the binding and physical removal of one or a plurality of soluble factors.
  • Blood is a complex and viscous biological fluid that contains many plasma proteins (e.g., albumin, globulins, fibrinogen), enzymes, metabolites, inorganic substances (e.g., calcium, sodium, magnesium, potassium), carbohydrates, lipids, vitamins, hormones, dissolved gases, leukocytes, erythrocytes, thrombocytes and other components (e.g., creatine, amino acids, choline, histamine, bilirubin).
  • plasma proteins e.g., albumin, globulins, fibrinogen
  • enzymes e.g., metabolites
  • inorganic substances e.g., calcium, sodium, magnesium, potassium
  • carbohydrates e.g., vitamins, hormones, dissolved gases, leukocytes,
  • the system disclosed herein is distinguishable from several extracorporeal technologies known in the art that employed systems for circulating whole blood through a device, which has the effect of concentrating target components in the blood path while the extracorporeal circuit is running.
  • devices that employ whole blood filtration include the Seraph 100 Microbind Affinity Blood Filter (Exthera Medical Corporation, Martinez CA) and CytoSorb adsorber (CytoSorbents Corporation, Princeton, NJ).
  • the present invention advantageously facilitates real-time extraction of target molecules while also avoiding cellular aggregation and activation that can take place in systems that process whole blood.
  • an extracorporeal device disclosed herein is coupled to an industry-standard apheresis machine using apheresis machine tubing sets, intravenous tubing extension sets, fluidic tubing adapters, filters, stopcocks, and/or other elements.
  • the procedure involves gaining access to the circulatory system of a subject via an arteriovenous fistula, an arteriovenous graft, or a dual lumen hemodialysis catheter.
  • a typical apheresis machine extracts whole blood for a subject and separates the blood into components, for example plasma, which is treated by passage through a cartridge to remove a target material.
  • an apheresis machine comprises a commercially available apheresis system, for example, a Terumo BCT Spectra Optia® System or a Fresenius AmicusTM System.
  • Apheresis machines may use centrifugal or membrane separation techniques for plasma separation from whole blood of a subject in need of treatment.
  • An apheresis machine is operated using the manufacturer's instructions for the specific machine.
  • An apheresis machine can be used to achieve selective removal of disease-mediating substances and molecules without the requirement for replenishing the subject with human plasma products.
  • the apheresis machine can be configured to allow a defined number of plasma volumes (PV) to be treated during treatment of a subject, for example, 1 PV, 2 PV, 3 PV, or more, wherein the total volume of the subject's plasma is treated once, twice, three times, or more.
  • PV plasma volumes
  • an extracorporeal device is inserted in-line in the secondary circuit of an apheresis machine.
  • the apheresis machine facilitates intravenous removal of blood from a subject and separates the blood into plasma and cellular fractions.
  • a plasma fraction then pumped through an extracorporeal device disclosed herein, wherein the plasma is exposed to a substrate comprising an immobilized ligand (i.e., a therapeutic antibody) having affinity for a soluble factor comprising an antigen (i.e., a soluble antigen). Passage of the plasma through the substrate causes the antigen to bind to the therapeutic antibody thereby reducing the load of the soluble factor in the effluent.
  • the plasma is then recombined with the cellular and other plasma components and reintroduced into the circulatory system.
  • extracorporeal devices comprising other therapeutic antibodies can be utilized for the binding and removal of distinctive antigens from the circulatory system.
  • Embodiments of the invention disclose an extracorporeal device comprising a cartridge.
  • Certain embodiments of the invention utilize a cartridge comprising a commercial hemodialysis cartridge or a plasma filter.
  • the overall dimensions of a cartridge can be selected to provide a volume and/or a surface area for contacting and removing a soluble factor from blood or plasma.
  • the performance of a cartridge for removing a target molecule from circulation is affected by variables including but not limited to the cartridge length, the cross-sectional area, and the diameter and/or surface area of internal membranes or fibers, if applicable.
  • a cartridge comprises a housing, an inlet that receives a blood or a blood component such as plasma, an internal chamber or compartment configured to receive the blood or plasma from the inlet, and an outlet configured to pass the blood or plasma from the cartridge.
  • the housing, inlet and outlet may be configured to couple with the flow line of an apheresis machine following separation of the subject's blood into plasma and cellular fractions by the machine.
  • the housing may comprise an elongated tubular structure with a circular cross-sectional shape that contains the internal chamber or compartment including the substrate.
  • the internal compartment of the cartridge is coupled to the inlet to receive plasma from the inlet.
  • the internal compartment may comprise a substrate to which at least one ligand is coupled (i.e., at least one therapeutic antibody) and is thereby configured to remove a soluble factor from blood or plasma.
  • a cartridge also comprises one or more filters, end caps, access ports, and/or elution ports.
  • the cartridge is configured with filters that serve as porous barriers to retain the substrate in the internal chamber. The filters may be positioned perpendicularto the plasma flow path and proximate to the inlet and the outlet in a manner that separates the internal chamber from the inlet and the outlet on both ends of the housing.
  • the pores in the filters may be appropriately sized with average pore diameters that prevent escape or leaching of a substrate such as a bead, particle, or another resin or matrix material, out of the device during an extracorporeal procedure.
  • a substrate such as a bead, particle, or another resin or matrix material
  • the average pore diameter of a filter may be ⁇ 200 microns, ⁇ 100 microns, ⁇ 50 microns, ⁇ 10 microns, ⁇ 5 microns, ⁇ 2 microns, or smaller.
  • a housing includes end caps at either end of housing that are fitted or affixed to ensure sterility and that may contact the inlet and the outlet and/or that terminate at inlet and the outlet.
  • an elution port is configured to facilitate removal of all or part of a substrate, a therapeutic antibody ligand, a captured soluble factor, and/or a combination thereof, from the compartment.
  • an elution port is configured to allow introduction of a reagent or buffer into the internal compartment of the cartridge.
  • an extracorporeal device is configured to facilitate a flow rate of through the system of between about 10 mL/min and about 300 mL/min. In some embodiments, the flow rate may be between about 25 mL/min and about 50 mL/min. In other embodiments, an extracorporeal device comprises the appropriate specifications and features including internal diameter to facilitate faster flow rates of blood or plasma through the system. In certain embodiments, the flow rate may be between about 50 mL/min and about lOOmL/min, or between about 100 mL/min and 200 mL/min. In certain embodiments, a flow rate for operating the system in conjunction with an apheresis machine is selected that optimizes capture efficiency of a soluble factor by the extracorporeal device.
  • a cartridge housing comprises one or more of the following materials: ECTFE (ethylene-chlorotrifuluoroethylene copolymer, halar ECTFE, ETFE (ethylenetetrafluoroethylene), tefzel ethylene tetrafluoroethylene (ETFE), FER (fluorinated ethylene polypropylene), HDPE (high density polyethylene), LDPE (low density polyethylene), PC (polycarbonate), Makrolon polycarbonate, PEI (polytheterimide), PET (polyethylene terephthalate), PETG (polyethylene terephthalate copolymer), PFA (polyfluoroalkoxy), Teflon PFA, PMMA (polymethyl methacrylate), PMP (polymethypentene), polypropylene, PPCO (polypropylene copolymer), polystyrene, PSF (polysulfone), PTFE (polytetrafluoroethylene), SAN
  • a substrate comprises one or more of the following materials: agarose, Sepharose, cellulose, pore glass, silica, acrylamide derivatives polyacrylamide beads, trisacryl, sephacryl, an Ultrogel® AcA chromatography sorbent (Pall Corporation), azlactone beads, methacrylate derivatives, a TSKgel® chromatography gel (Tosoh Corporation), a TOYOPEARL® HW polymer gel (Tosoh Corporation), HEMA (2 hydroxyethyl methacrylate, poly (2 hydroxyethyl methacrylate), Eupergit, polystyrene and its derivatives, Poros, polyether sulfone, a polysaccharide, polytetrafluoroethylene, polysulfone, polyester, polyvinylidene fluoride, polypropylene, poly (tetrafluoroethylene-co-perfluoro(alkyl vinyl ether)), polycarbonate, polyethylene,
  • the solid support may be formed by plates, membranes, beads, ceramics, and/or other components.
  • a substrate comprises Sepharose beads, a size exclusion chromatography resin comprising a cross-linked agarose matrix.
  • a substrate comprises a ligand that is configured to bind to a soluble factor in blood or plasma and retain the soluble factor within the internal compartment of the cartridge.
  • a ligand comprises a therapeutic antibody or an antigen-binding portion thereof.
  • a ligand comprising a therapeutic antibody has an affinity for an antigen in the low micromolar (IO -6 ) to nanomolar (IO -7 to IO -9 ) range.
  • a ligand comprising a therapeutic antibody has an affinity for an antigen in the picomolar (10 12 ) range.
  • a therapeutic antibody is selected for its affinity and binding specificity for a soluble factor in plasma.
  • a therapeutic antibody has binding specificity and affinity for a soluble factor comprising a noncell-associated antigen in plasma. In yet other embodiments, a therapeutic antibody has binding specificity and affinity for an antigen that is a component of a multi-antigenic entity in plasma, such as a microparticle or an exosome.
  • a therapeutic antibody has binding specificity and affinity for a soluble antigen, wherein contact of the therapeutic antibody with the soluble antigen leads to affinity capture of an entity in blood or plasma comprising the soluble antigen, and wherein the entity comprises one or more of the following: a microparticle, an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular nanoparticle (such as an exomere or a supermere), an apoptotic body, a protein, a glycoprotein, and/or an anti-drug antibody.
  • a substrate is configured with two or more therapeutic antibodies, wherein each therapeutic antibody has binding specificity and affinity for the same soluble antigen.
  • a substrate is configured with a plurality of therapeutic antibodies, wherein each therapeutic antibody has binding specificity and affinity for the same soluble antigen, and wherein each therapeutic antibody has binding specificity and affinity for a distinct epitope of the soluble antigen. Targeting two distinct epitopes may be advantageous for improving the capture of a soluble factor from plasma.
  • a substrate is configured with a plurality of therapeutic antibodies, wherein each therapeutic antibody exhibits binding specificity and affinity for a different soluble antigen.
  • an extracorporeal device comprising a hollow fiber membrane or filter, wherein whole blood enters the inlet and plasma components are separated from whole blood within the device, wherein the separated plasma components are then subjected to an affinity capture step for the removal of one or more soluble factors.
  • the hollow fibers may comprise one or more different materials including but not limited to cellulose, cellulose ester, polysulfone, polyethersulfone (PES), polymethylmetacrilate (PMMA), polyamide, nitrogen-containing polymers, glass, silica, cellulose acetate, polyvinyldene fluoride (PVDF), poly (vinyl chloride) (PVC), polytetrafluoroethylene (PTFE), poly ester, ceramic, polyimide, polyetherimide, polyethyleneimine-functionalized polyamide imide (Torlonml) and/or poly (vinyl alcohol) (PVA).
  • PVDF polyvinyldene fluoride
  • PVC poly (vinyl chloride)
  • PTFE polytetrafluoroethylene
  • PVA poly (vinyl alcohol)
  • an extracorporeal device comprises a housing having a receiving space and at least one hollow fiber extending longitudinally through at least a portion of the receiving space of the housing.
  • the at least one hollow fiber is configured to receive the whole blood comprising both cellular elements and plasma components.
  • the device includes a substrate (e.g., a bead) within the receiving space and external to the hollow fibers.
  • a ligand comprising a therapeutic antibody is conjugated or immobilized to the substrate to create an affinity capture surface for one or a plurality of soluble factors within the receiving space.
  • a hollow fiber may include a plurality of pores configured to retain the cellular elements of the blood within the hollow fiber while allowing the plasma components from blood to pass from the hollow fiber to the receiving space of the housing to contact the substrate and the ligand.
  • the pores in the hollow fibers have diameters between 20-600 nm or between 20- 1,000 nm to facilitate the passage of plasma components comprising a soluble factor from the blood path into the receiving space comprising a substrate and at least one ligand and to exclude the passage of cellular elements.
  • an average or mean size of pores in the hollow fibers is between 100-200 nm or between 100-500 nm.
  • the pores in the hollow fibers are appropriately dimensioned to permit passage of a soluble factor into the receiving space comprising the substate and a therapeutic antibody ligand.
  • the pore sizes are configured to allow a plasma component comprising a soluble factor to access the receiving space comprising a therapeutic antibody ligand.
  • the pore sizes are configured to allow a multi-protein entity comprising a soluble factor to access the receiving space.
  • the plasma component may then pass back to the hollow fiber through one or more pores to rejoin the bloodstream, yielding a filtered or treated bloodstream, which may then exit the device.
  • a hollow fiber filter may be used as part of a standard dialysis system or plasmapheresis system in the treatment of a subject in need thereof.
  • the device may be connected to one or more pumps to facilitate passage of the blood through the device or the hollow fibers. Blood may be passed back through the device several times during each treatment of a subject's blood. For example, a treatment session with an extracorporeal device may involve circulating a subject's bloodstream for a defined duration, for example, for up to 6 hours, to facilitate increase the amount of a soluble factor removed from the plasma component.
  • an extracorporeal device is configured to reduce the levels of a soluble factor in plasma of a subject with a disease or condition to the levels of the soluble factor that are typically present in a pre-disease state in a subject or in a cohort of subjects.
  • an extracorporeal device is configured to reduce or deplete the concentrations of one or a plurality of soluble factors having concentrations in blood or a plasma that are positively correlated with a disease state or a symptom thereof.
  • one or multiple procedures using an extracorporeal device are performed to reduce the concentration of a soluble factor in blood or plasma.
  • an extracorporeal device is configured for affinity capture of an entity in blood or plasma comprising the soluble factor, wherein the entity comprises one or more of the following: a microparticle, an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular a nanoparticle (e.g., an exomere, a supermere), an apoptotic body, a protein, a glycoprotein, a glycolipid, and/or an antidrug antibody.
  • the entity comprises one or more of the following: a microparticle, an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular a nanoparticle (e.g., an exomere, a supermere), an apoptotic body, a protein, a glycoprotein, a glycolipid, and/or an antidrug antibody.
  • an extracorporeal device is configured to reduce the plasma levels of one or more of the following molecules in a subject with a disease or condition: an antibody, a tumor-associated antigen, a tissue-specific antigen, an angiogenesis-related protein, an immune checkpoint protein, a viral glycoprotein, a pathogen-derived protein, a bacterial toxin, a complement component, an integrin, a cytokine, a cytokine receptor, a chemokine, a chemokine receptor, a lymphocyte receptor, a lymphocyte-expressed ligand, a B-cell receptor component, a transmembrane glycoprotein, a cell adhesion molecule, a ganglioside, a receptor tyrosine kinase, a fibroblast growth factor, a transforming growth factor superfamily protein, a microtubule-associated protein, a serine protease, or a coagulation factor.
  • an antibody a tumor-associated antigen, a tissue-
  • an extracorporeal device may be configured to reduce the plasma levels of one or more of the following antigens: PD-L1, PD-1, CTLA-4, CD137, CD20, HERZ, TROP-2, CD37, CD38, disialoganglioside GD2, EPCAM, CD30, CD33, CD22, CD19, CD79b, BCMA, CD123, B7-H3, Nectin- 4, CD73, CD39, ILT2, ILT4, tissue factor, FRalpha, CEACAM5, c-Met, ROR-1, NaPi2b, VISTA and CCL18.
  • antigens PD-L1, PD-1, CTLA-4, CD137, CD20, HERZ, TROP-2, CD37, CD38, disialoganglioside GD2, EPCAM, CD30, CD33, CD22, CD19, CD79b, BCMA, CD123, B7-H3, Nectin- 4, CD73, CD39, ILT2, ILT4, tissue factor, FR
  • antibodies are conventionally provided as pharmaceutical formulations for administration into a site of the body via one of many possible routes, most frequently intravenously (e.g., by infusion) or subcutaneously.
  • a therapeutic antibody may also be administered BY one of the following routes: intramuscular, intraperitoneal, oral, sublingual, transdermal, intracavity, intravitreal, or inhalation (aerosol).
  • therapeutic antibody administration by infusion or other delivery routes is performed according to standard medical practices.
  • a therapeutic antibody is prepared as a pharmaceutical formulation for administration as a drug and is prepared accordingly using methods known to those of ordinary skill in the art.
  • a therapeutic antibody may be prepared as a biologic formulation as a liquid or lyophile for reconstitution and may be concentrated in a buffer solution with added excipients to confer stability.
  • a formulation of a therapeutic antibody is prepared as a specific concentration, pH, and viscosity using methods known to one of skill in the art.
  • a therapeutic antibody drug may be prepared using a specific drug delivery system that is designed to promote drug accumulation in the target tissue, to alter the pharmacokinetics, and to improve the efficacy.
  • a therapeutic antibody may be prepared with carriers to protect the molecules or compounds against rapid elimination form the body, for example using microencapsulated delivery systems comprising biodegradable and biocompatible polymers and other pharmaceutically acceptable carriers.
  • a pharmaceutical formulation comprising a therapeutic antibody is prepared to be compatible with its intended route of administration.
  • a therapeutic antibody drug for commercial use may be available from the manufacturer as a lyophilized powder or in a buffered solution that may be ready-to-use (e.g., for subcutaneous administration) or may require reconstitution into saline or equivalent to a specified concentration prior to administration to a subject (i.e., for intravenous administration).
  • Such preparations may be dispensed into ampules, disposable syringes, or vials made of glass, plastic, or other materials.
  • Certain embodiments of the invention provide compositions and solutions of therapeutic antibodies that are suitable for incorporation into an extracorporeal device.
  • a solution comprising a therapeutic antibody is prepared in one of the following buffers: morpholino propanesulfonic acid buffer (MOPS), TRIS, sodium phosphate, and/or sodium citrate.
  • MOPS morpholino propanesulfonic acid buffer
  • a composition or solution may comprise additional components needed to maintain physical and chemical integrity of the antibody, which may comprise one or more components such as excipients, buffers, or surfactants.
  • a substrate comprising a therapeutic antibody that is irreversibly bound to a substrate.
  • a therapeutic antibody is covalently or non-covalently attached to a substrate.
  • a therapeutic antibody is immobilized on or otherwise attached to a substrate using one or more of the following chemical coupling methods: amine reductive chemistries, cyanogen bromide (CNBr), N-hydroxy succinimide esters, carbonyl diimidazole, reductive amination, 2-fluoro-l-methylpyridinium (FMP) activation, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-mediated amide bond formation organic sulfonyl chlorides tosyl chloride and tresyl chloride, divinylsulfone, azlactone, cyanuric chloride (trichloror-s-triazine), sulfhydryl reactive
  • a therapeutic antibody is covalently attached to a bead or another structure or resin, for example, through amines or thiol moieties.
  • a substrate comprising a bead such as Sepharose to which a therapeutic antibody or a portion thereof is covalently attached, for example, using reductive amination chemistry to couple the therapeutic antibody to a bead using reagents and protocols that are known in the art.
  • a substrate is prepared using methods for directional immobilization of a therapeutic antibody onto a bead, which may be performed to improve the uniformity of therapeutic antibody orientation on the substrate surface.
  • methods and chemistries for achieving directional antibody orientation may employ click chemistry, site-directed conjugation methods such as affinity capture tags, or material-binding peptides fused to an antibody to promote directional attachment to a particular solid support.
  • site-directed conjugation methods such as affinity capture tags, or material-binding peptides fused to an antibody to promote directional attachment to a particular solid support.
  • conjugation of a therapeutic antibody to a substrate or support can be optimized to ensure that the binding site of the therapeutic antibody for its intended target is not affected by the chemistries for substrate preparation.
  • Certain embodiments of the invention thereby provide substrates comprising one or more immobilized or attached therapeutic antibodies for exposing blood or plasma to a therapeutic antibody extracorporeally.
  • a therapeutic antibody is immobilized to the substrate to prevent leaking or loss of the therapeutic antibody or the complex of the therapeutic antibody with the soluble factor out of the device and into the plasma flow path during an extracorporeal procedure.
  • the devices disclosed herein can be configured to avoid introduction or leakage of pharmacologically relevant amounts of a therapeutic antibody into the bloodstream during an extracorporeal procedure. This aspect of the invention can ensure that the devices disclosed herein are directed toward extracorporeal contact of plasma with a therapeutic antibody rather than inadvertently introducing a therapeutic antibody into the body.
  • a therapeutic antibody is conjugated to a substrate via a bond or interaction, for example, via a covalent bond, non-covalent bond, ionic bond, hydrophobic bond, electrostatic bond, and/or another bond, wherein the bond provides resistance to dissociation of the therapeutic antibody from the substrate surface.
  • Dissociation of a therapeutic antibody from a substrate can be measured by quantifying the therapeutic antibody that has leaked or leached into blood or plasma at one or more specific time points during or after an extracorporeal procedure, which may be expressed in units of ng/mL or ng/min (i.e., a dissociation rate).
  • a substrate comprises a therapeutic antibody, wherein the therapeutic antibody is resistant to dissociation, wherein resistance to dissociation is delineated as a dissociation rate of a therapeutic antibody into plasma of ⁇ 200 ng/min, ⁇ 100 ng/min, ⁇ 50 ng/min, ⁇ 20 ng/min, or ⁇ 10 ng/min, or lower during operation of the extracorporeal device.
  • a ligand undergoes modifications to facilitate attachment or immobilization to a substrate.
  • a linking agent ora linker is used to attach a ligand to the substrate surface.
  • avidin or streptavidin
  • the therapeutic antibody ligand to be attached is biotinylated.
  • biotinylated ligand contacts the avidin/streptavidin binding and attachment to the substrate surface is facilitated.
  • any remaining active binding surfaces can be blocked using a solution of ethanolamine, human albumin, or a similar blocking material.
  • the blocking step can be performed at the time of performance of an extracorporeal procedure (i.e., apheresis) by priming the device with a solution of human albumin or similar blocking solution.
  • an extracorporeal device disclosed herein comprises one or a plurality of full-size therapeutic antibodies, which are typically defined as having molecular weights of approximately 150 kDa and having structurally intact and/or full-length immunoglobulin domains.
  • a device comprises a monoclonal antibody, a polyclonal antibody, a bispecific or a multivalent and/or multispecific antibody.
  • the monoclonal antibody or antigen-binding fragment is a fully human antibody or antigen-binding region or domain.
  • the monoclonal antibody or antigen-binding region or domain is a chimeric or synthetic antibody.
  • a therapeutic antibody may also comprise an engineered antibody, which may comprise an array of antibody formats including chimeric antibodies and grafted molecules.
  • a therapeutic antibody comprises a variant of a full-size antibody or a portion thereof that has one or more amino acid substitutions or modifications from an original antibody.
  • a substitution may entail replacement of one amino acid for another amino acid that brings a biological, chemical, or structural change to the antibody.
  • an extracorporeal device disclosed herein comprises one or more of the following therapeutic antibodies or portions thereof: Serplulimab, Sugemalimab, Pozelimab, Concizumab, Elranatamab, Cosibelimab, Rozanolixizumab, Talquetamab, Epcoritamab, Lebrikizumab, Trastuzumab duocarmazine, Glofitamab, Mirikizumab, Donanemab, Lecanemab, Tislelizumab, Penpulimab, Sintilimab, Toripalimab, Omburtamab, Retifanlimab, Narsoplimab, Teplizumab, Ublituximab, Mirvetuximab soravtansine, Nirsevimab, Tremelimumab, Spesolimab, Teclistamab, Mosunetuzumab, Tixagevimab,
  • therapeutic antibodies that are available as pharmaceutical compositions have additional structural elements in addition to their antigen-binding sites.
  • the efficacy of therapeutic antibody drugs often involves induction of effector functions of antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and/or the direct induction of apoptosis, functions which rely on the non-antigen binding Fc region of the antibody.
  • a therapeutic antibody drug may further comprise a cargo, a payload, a radionuclide, a drug, a label, a toxin, a cytokine, an antigen, a superantigen or an additional material.
  • a therapeutic antibody may refer to a portion, domain, or region of a therapeutic antibody or an engineered version of a full-size therapeutic antibody. Such portions or domains can be readily constructed, expressed, and produced on a large-scale using methods known in the art.
  • an extracorporeal device disclosed herein comprises an antigen-binding portion, region, or domain of a full-size therapeutic antibody molecule.
  • an extracorporeal device comprises an antigen-binding portion of a full-size therapeutic antibody molecule and a deletion or truncation of the Fc region of a full-size therapeutic antibody molecule.
  • a portion or domain of a therapeutic antibody retains the affinity for a target antigen of the full-size therapeutic antibody, wherein the molecular weight of the portion or domain of the full-size therapeutic antibody may be ⁇ 150 kDa, ⁇ 100 kDa, ⁇ 50 kDa, ⁇ 20kDa, or ⁇ 10kDa.
  • Embodiments of the invention provide an extracorporeal device comprising an scFv, which comprises the complete antigen-binding domains of a whole antibody.
  • An scFv antibody typically consist of variable regions of heavy (VH) and light (VL) chains, joined together by a flexible peptide linker and having a molecular weight of approximately 25 kDa, which is much smaller than that of a full-length mAb.
  • Other embodiments of the invention provide an extracorporeal device comprising at least one CDR of a full-size therapeutic antibody.
  • an extracorporeal device comprises an antigen-binding portion or domain of a therapeutic antibody, for example, an scFv or an antigen-binding fragment (Fab).
  • an extracorporeal device comprises a therapeutic antibody format that differs from a full-size immunoglobulin domain structure and/or an antibody format that comprises additional proteins or moieties.
  • an extracorporeal device comprises an antibody-drug conjugate (ADC) or a portion or domain thereof for removal of a soluble factor from the circulatory system.
  • ADC antibody-drug conjugate
  • Antibody-drug conjugates are typically comprised of a tumor antigen-specific monoclonal antibody conjugated to a cytotoxic drug via a linker, where a linker is a biochemical compound connecting the antibody to a payload comprising a cytotoxic drug or a chemotherapy drug.
  • the cytotoxic agents may include calicheamycins, auristatin derivatives (monomethyl auristatin E and monomethyl auristatin F), maytansinoids, PBDS, duocarmycins, camptothecin derivatives and/or Pseudomonas exotoxin A (PE38).
  • calicheamycins auristatin derivatives (monomethyl auristatin E and monomethyl auristatin F)
  • maytansinoids PBDS
  • duocarmycins duocarmycins
  • camptothecin derivatives and/or Pseudomonas exotoxin A (PE38).
  • Pseudomonas exotoxin A PE38
  • an extracorporeal device comprises the unconjugated therapeutic antibody component of an antibody-drug conjugate which, in certain embodiments, excludes the cytotoxic payload of an intact antibody-drug conjugate.
  • Extracorporeal devices are also provided that comprise at least one antigen-binding portion/region of an antibody-drug conjugate, for example, an scFv, a Fab, and/or at least one CDR, or others.
  • an extracorporeal device comprises a therapeutic antibody with the same antigenic specificity as an ADC, wherein said therapeutic antibody is provided to remove one or more soluble factors that bind to the antibody-drug conjugate.
  • an extracorporeal device comprises a therapeutic antibody with an identical amino acid sequence as the antibody component of an antibody-drug conjugate or a corresponding antigen-binding portion or domain, wherein the therapeutic antibody is provided in an extracorporeal device to remove one or more soluble factors that bind to the antibody-drug conjugate.
  • an extracorporeal device may comprise an antibody component of an antibody-drug conjugate or a portion thereof with specificity for a soluble factor comprising one of the following antigens: CD3, CD19, CD20, CD22, CD30, CD33, CD79, Trop-2, BCMA, Tissue factor, Nectin-4, Folate receptor alpha (Fralpha), or HER2.
  • an extracorporeal device comprises the antibody component or a portion thereof of said antibody-drug conjugate.
  • the extracorporeal device comprises the antigen-binding portion or domain of an antibody-drug conjugate or a portion thereof.
  • the antibody-drug conjugte comprises one of the following drugs: gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, or inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, trastuzumab duocarmazine, BAT8001, mirvetuximab soravtansine, or SAR408701.
  • an extracorporeal device incorporates a commercial therapeutic antibody drug or a portion or a domain thereof for removal of one or more soluble drug antagonists or decoys of said antibody.
  • a therapeutic antibody is an original version (or originator) drug, which are considered reference drugs in biopharmaceutical practice since they represent the first antibody targeting a particular antigen or epitope.
  • an extracorporeal device comprises a biosimilar therapeutic antibody or a portion thereof, wherein a biosimilar theraeputic antibody refers to a generic version of an original antibody (or an "innovator" antibody, and in some cases, a marketed antibody) with the same amino acid sequence but produced from different clones and/or manufacturing processes.
  • an extracorporeal device comprises a biobetter antibody or a portion thereof, which may comprise an antibody that targets the same validated epitope as an original and/or marketed antibody, but has been engineered to have improved properties, for example, optimized glycosylation or an engineered Fc domain to increase the serum half-life upon administration as a drug.
  • an extracorporeal device comprises a second-generation, a third-generation antibody, or a subsequent version thereof, or a portion thereof.
  • a second-generation antibody may comprise a follow-up antibody from an original and marketed therapeutic antibody that is designed with improved variable domains (such as humanized or human variable domains or affinity matured CDRs).
  • a second-generation therapeutic antibody is directed against the same antigen but has alterations to variable domains that may decrease the immunogenicity of the antibody, may target distinct epitopes with different affinity for the target antigen, and/or may comprise different antibody formats from the original antibody.
  • a therapeutic antibody is a third-generation antibody; for example, an antibody that targets a distinct epitope of an antigen relative to an original marketed antibody but retains the specificity and affinity for the antigen.
  • Table 1 Exemplary Therapeutic antibodies for Extracorporeal Devices
  • Table 1 provides non-limiting examples of therapeutic antibodies contemplated for use in the disclosed extracorporeal therapies.
  • the art provides more than one therapeutic antibody drug against certain antigenic targets, wherein drug formulations may employ distinctive specificities for certain epitopes and/or variable effector functions encoded in the Fc regions.
  • Certain embodiments provide an extracorporeal device comprising a first therapeutic antibody or a portion thereof selected from Table 1 for treating the blood or plasma of a subject prior to or following administration of a drug formulation of a second therapeutic antibody selected from Table 1 into the body of the subject, wherein the first and the second therapeutic antibodies are selected to have binding specificity and affinity for the same antigen.
  • the first therapeutic antibody and the second therapeutic antibody selected from Table 1 are identical.
  • an extracorporeal device comprises an immune checkpoint inhibitor antibody, wherein the device is configured for the removal of a soluble immune checkpoint protein from blood or plasma of a subject.
  • Certain embodiments provide an extracorporeal device for treatment of a subject with cancer, wherein the device comprises one or more of the following therapeutic antibodies: atezolizumab, durvalumab, avelumab, sugemalimab, and/or cosibelimab, and wherein the device is configured to remove the soluble form of the PD-L1 antigen priorto orfollowingthe administration of one of these same antibodies to the subject as a pharmaceutical composition.
  • an extracorporeal device is configured to achieve a reduction in the amount or concentration of one or a plurality of soluble factors in blood or plasma.
  • the amount or concentration of one or a plurality of soluble factors is measured at time points before, during, or after an extracorporeal procedure, or at a combination of time points.
  • the rate at which a soluble factor is depleted from plasma can also be determined by plotting the reduction in concentration or quantity against time.
  • a rebound in the amount or concentration of a soluble factor in blood is a by-product or reaction to exposure to an administered therapeutic antibody drug.
  • cessation of treatment with a therapeutic antibody drug can lead to an increase in the circulating concentration of a soluble factor.
  • resistance to a therapeutic antibody drug may manifest as an increase in the circulating concentration of a soluble factor.
  • aspects of the invention involve monitoring an increase in the amount or concentration of a soluble factor following the completion of an extracorporeal procedure or at one or more time intervals in between two extracorporeal procedures.
  • the rate of increase in the concentration of soluble factor in plasma may be determined by plotting the increase in concentration orquantity against time.
  • the rate at which a soluble factor in blood rebounds to pre-treatment levels can be used to inform the frequency or duration for performance of an extracorporeal procedure.
  • the rebound rate of a soluble factor is determined to inform the timing for performance of an extracorporeal procedure relative to the administration of a therapeutic antibody drug.
  • aspects of the invention involve determining the secretion rate, elimination rate, and/or the half-life of a soluble factor.
  • the half-life of an extracellular vesicle or an exosome may be determined in a subject or for a group of subjects having a particular disease or condition.
  • a short-half-life of an extracellular vesicle or an exosome is defined as ⁇ 1 hour, ⁇ 3 hours, ⁇ 6 hours, or ⁇ 12 hours.
  • a short-half-life of an extracellularvesicle or an exosome is used to indicate the need to provide an extracorporeal therapy and a therapeutic antibody drug within a close time frame to ensure adequate clearance of the former at the time point of therapeutic antibody drug exposure.
  • the systems and devices of the invention are applied on the same day, or within 1-2 hours, 2-4 hours, 4-8 hours, or 8-12 hours prior to therapeutic antibody drug administration.
  • a therapeutic antibody drug is preferably given prior to the rebound of a soluble factor to a clinically relevant level and/or above a pre-defined concentration in a subject or in a group of subjects.
  • a soluble factor is defined as elevated based on a measurement exceeding the mean or average concentration of a soluble factor in one or more disease-free subjects.
  • the therapeutic regimen reduces the rebound levels of the soluble factor that are measured between extracorporeal procedures. This may be reflected as lower soluble factor levels prior to the initiation of a subsequent extracorporeal procedure or during a subsequent extracorporeal procedure.
  • kits that are useful for practicing the treatment methods described herein.
  • a kit comprises components that are needed for delivering a therapeutic regimen of the invention to a subject, wherein a therapeutic regimen comprises administration of at least one dose of a therapeutic antibody drug to a subject and administration of at least one procedure with an extracorporeal device to the same subject.
  • a kit comprises at least one extracorporeal device described herein, wherein each extracorporeal device comprises at least one therapeutic antibody.
  • a kit comprises at least one therapeutic antibody provided as a drug formulation (i.e., a pharmaceutical composition).
  • kits comprising therapeutic antibodies in two distinct formats, wherein a first therapeutic antibody is provided as a dose of a drug formulation for targeting an antigen in a target tissue and a second therapeutic antibody is provided in an extracorporeal device for targeting a soluble form of the same antigen.
  • the kit provides a plurality of doses of a drug formulation comprising the first therapeutic antibody and/or a plurality of extracorporeal devices comprising the second therapeutic antibody for the purpose of performing repeat therapies for the subject, and wherein the plurality of doses of the drug and the plurality of extracorporeal devices all comprise therapeutic antibodies that are directed against the same antigen.
  • an extracorporeal device comprising a therapeutic antibody is provided to improve the delivery and/or the binding a drug formulation comprising a therapeutic antibody to an antigen in a target tissue.
  • the kit contains instructions for administering the drug formulation comprising the first therapeutic antibody and/or for performing a procedure with an extracorporeal device comprising the second therapeutic antibody.
  • instructions are provided related to the timing or sequence of performance of one or more extracorporeal procedures relative to administration of one or more doses of a drug formulation.
  • the kit provides instructions for first administering a drug formulation comprising a first therapeutic antibody into the body of the subject and subsequently applying an extracorporeal device comprising a second therapeutic antibody to treat the blood or plasma of the subject.
  • kits are provided for first applying an extracorporeal device comprising the second therapeutic antibody to treat the blood or plasma of the subject and subsequently administering a drug formulation comprising the first therapeutic antibody into the body of the subject.
  • the kit or any component thereof may be packaged in combination with one or more containers, devices, reagents, medical disposables such as sterile syringes and needles, or other accessories needed to deliver the treatments.
  • a kit comprises accessories for performing an extracorporeal procedure comprising a blood access catheter, a blood tubing set, a blood connector, accessories for coupling the device to an apheresis system, other components, and/or combinations thereof.
  • kits comprising at least one extracorporeal device, wherein the extracorporeal device comprises a therapeutic antibody, and at least one dose of a therapeutic antibody drug that is appropriately formulated for direct administration to a subject, for example, by infusion, injection subcutaneously or intramuscularly, or by another administration route.
  • a kit is provided that contains a drug formulation comprising a first therapeutic antibody with binding specificity for an immune checkpoint protein and an extracorporeal device comprising a second therapeutic antibody with binding specificity for the same immune checkpoint protein (for example, PD-1. PD-L1, or CTLA-4).
  • kits comprising a plurality of drug formulations, wherein each drug formulation comprises a different therapeutic antibody drug, and wherein each therapeutic antibody drug has binding specificity for a different antigen.
  • a kit may also comprise a plurality of extracorporeal devices, wherein each extracorporeal device comprises a different therapeutic antibody, and wherein each therapeutic antibody has binding specificity for a different antigen.
  • Such a kit may be useful for removal of more than one soluble factor from blood or plasma.
  • a kit of the invention may contain an extracorporeal device comprising a therapeutic antibody and a drug formulation comprising a therapeutic antibody, wherein the antibodies bind to different antigens in a biological pathway, for example, one antibody binds to a ligand and the other antibody binds to its receptor.
  • a kit may contain an extracorporeal device comprising a therapeutic antibody and a drug formulation comprising a therapeutic antibody, wherein the former comprises a therapeutic antibody directed against PD-L1 and/or PD-L2 and the latter comprises a therapeutic antibody drug directed against PD-1.
  • kits comprising a plurality of extracorporeal devices, wherein each extracorporeal device is configured to remove one or a plurality of different antigens from blood or plasma.
  • a kit of the invention may also comprise one or a plurality of therapeutic antibody drugs having binding specificities for different antigens .
  • a kit comprises (a) a first therapeutic antibody in a drug formulation, wherein the formulation is provided to deliver a therapeutic antibody to a target tissue, and wherein the therapeutic antibody is selected to bind to an antigen in a target tissue; and (b) a second therapeutic antibody in an extracorporeal device, wherein the extracorporeal device is configured to receive blood or plasma comprising a soluble factor, wherein the second therapeutic antibody is selected to bind the soluble factor in blood or plasma and to retain the bound soluble factor, and wherein the blood or plasma obtained after exposure to the second therapeutic antibody has a reduced amount of a soluble factor.
  • the first therapeutic antibody and the second therapeutic antibody have binding specificity for the same antigen.
  • the first therapeutic antibody and the second therapeutic antibody in the kit have binding specificity for the same epitope of an antigen.
  • the kit is applied to treat a subject by first administering a drug formulation comprising a therapeutic antibody into the body of the subject and subsequently applying an extracorporeal device comprising a therapeutic antibody to treat the blood or plasma of the subject.
  • the kit provides an extracorporeal device comprises a cartridge, and wherein the cartridge comprises a substrate to which a therapeutic antibody is immobilized to bind at least one soluble factor from blood or plasma and retain the soluble factor within the cartridge.
  • kits that is useful for removing a soluble factor from blood or plasma that is present in a plurality distinct circulating forms and as structurally heterogeneous entities. Accordingly, certain embodiments disclose a kit comprising an extracorporeal device that is configured to remove an entity from blood or plasma that comprises a soluble factor, wherein the entity comprises one or more of the following: a microparticle, an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular a nanoparticle, an apoptotic body, a protein, a glycoprotein, a glycolipid, or an anti-drug antibody.
  • the kit provides a plurality of drug formulations comprising one or more therapeutic antibodies and/or a plurality of extracorporeal devices comprising one or more therapeutic antibodies.
  • a kit may be useful for extracorporeal removal of more than one soluble factor from blood or plasma.
  • kits that are useful for selecting a subject to receive treatment with an extracorporeal device of the invention. Such a kit may also be useful for determining the timing or frequency for delivery of extracorporeal therapy; for example, for clinical decision making in selecting a subject for further or additional treatment sessions at a particular point in time.
  • a kit comprises materials for performing a biomarker assay for the presence and/or concentration of at least one soluble factor comprising an antigen in plasma or serum of a subject.
  • a kit comprises at least one enzyme- linked immunosorbent assay (ELISA) kit, at least one MSD assay, or equivalent.
  • ELISA enzyme- linked immunosorbent assay
  • an immunoassay kit for detection of a panel of related molecules to determine which soluble antigens are present in the blood of a subject.
  • a kit may also contain assay plates, disposables, reagents, buffers, and instruments required to facilitate performance of the assays.
  • a kit comprises at least one extracorporeal device described herein, which may be applied for removal of one or more soluble factors that have been identified or quantified in the biomarker assay.
  • Some embodiments also provide a plurality of extracorporeal devices for performing repeat therapies, as needed based on the levels of a soluble factor present in blood.
  • a kit also comprises accessories for performing an extracorporeal procedure comprising a blood access catheter, a blood tubing set, a blood connector, and/or other materials needed to perform the procedure.
  • instructions are provided for performing the biomarker assay and/or for operation and use of the extracorporeal device and the apheresis machine.
  • Embodiments of the invention provide one or more corresponding dose units of a therapeutic antibody drug in the appropriate formulation and vial for administration to a subject; for example, one dose of drug may be provided for each extracorporeal device in the kit.
  • kits for harvesting and assessing disease-related biomarkers from a subject undergoing treatment with a therapeutic regimen of the invention may be useful for assaying the soluble factors that were captured by an extracorporeal device during a subject's treatment session.
  • Certain embodiments provide a kit comprising materials and reagents for elution and/or for analysis of the recovered materials from a used extracorporeal device after treatment of a subject.
  • the kit comprises containers, tubes, reservoirs, buffers, chemicals, solvents, solutions, laboratory disposables, and other materials needed to perform an elution of one or a plurality of soluble factors captured in a used extracorporeal device.
  • a saline buffer or equivalent is provided to wash the used extracorporeal device by running a defined volume of solution through the device.
  • a ready-to-use elution buffer is provided that is suitable for dislodging complexed soluble antigen-antibody from a substrate in the device or for dissociating an antigen bound to an antibody within the device.
  • elution buffers may include 0.1 M glycine-HCL at pH 2.5-3.0, amine-containing buffer at pH 2.8, or a near-neutral (pH 6.6) high-salt buffer.
  • the most appropriate elution buffer may be determined by one of ordinary skill in the art by optimizing the pH, ionic strength, and the content of chaotrope(s) and/or denaturant(s) in the buffer, taking into consideration the properties of the therapeutic antibody that is immobilized in the device.
  • instructions may be provided for handling the post-treatment extracorporeal device and/or for performing an elution procedure. Materials and instructions may also be provided for storing the post -treatment cartridge prior to elution and analysis.
  • the kit comprises an assay system for identifying or quantifying the recovered material, for example, an immunoassay (ELISA, MSD, or equivalent), which may be used to assess the soluble factor(s) present in the subject.
  • the kit may also contain assay plates, disposables, reagents, and instruments required to facilitate performance of the assays.
  • the present invention provides methods for addressing the clinical limitations of therapeutic antibody drugs.
  • Certain therapeutic antibody drugs exhibit limited distribution to the target tissue, necessitating the delivery of a higher dose and increasing the adverse events and toxicities that may be experienced.
  • its efficacy may be compromised, as may be monitored based on clinical endpoints related to amelioration or control of the disease for the subject or the disease.
  • Therapeutic antibody drugs are also hampered by the emergence of drug resistance factors that have been molecularly and functionally characterized.
  • the present invention discloses methods that can be deployed to remove or reduce the drug antagonists or decoys that are present in blood or plasma prior to administration of a therapeutic antibody drug.
  • the present invention also provides methods for performing extracorporeal procedures to achieve the removal of drug antagonists or inhibitors that arise during or following therapeutic antibody exposure including anti-drug antibodies as well as other soluble "decoy" molecules involved in therapy resistance.
  • Embodiments of the invention provide devices and methods for clearing or reducing the concentration of one or a plurality of soluble factors from the circulatory system, which may be defined as antigens that bind and sequester a therapeutic antibody drug and, in some cases, flag the therapeutic antibody drug for elimination from the circulatory system through a variety of possible clearance mechanisms, possibly also reducing the drug's half-life.
  • a soluble factor is non-cell associated or free in circulation.
  • a soluble factor is a component of another circulating entity, wherein the soluble factor is geometrically oriented or physically displayed on the circulating entity to be accessible to an administered therapeutic antibody drug.
  • methods are provided for the removal of a molecular entity from blood or plasma that comprises a soluble factor, wherein the entity comprises one or more of the following: a microparticle, an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular a nanoparticle (e.g., an exomere or a supermere), an apoptotic body, a protein, a glycoprotein, a glycolipid, and/or an anti-drug antibody.
  • a microparticle an extracellular vesicle, an exosome, a microvesicle, an ectosome, a non-vesicular extracellular a nanoparticle (e.g., an exomere or a supermere), an apoptotic body, a protein, a glycoprotein, a glycolipid, and/or an anti-drug antibody.
  • the methods of the invention are applicable for removing a soluble factor that comprises one or more of the following molecules: an antibody, a tumor- associated antigen, a tissue-specific antigen, an angiogenesis-related protein, an immune checkpoint protein, a viral glycoprotein, a pathogen-derived protein, a bacterial toxin, a complement component, an integrin, a cytokine, a cytokine receptor, a chemokine, a chemokine receptor, a lymphocyte receptor, a lymphocyte-expressed ligand, a B-cell receptor component, a transmembrane glycoprotein, a cell adhesion molecule, a ganglioside, a receptor tyrosine kinase, a fibroblast growth factor, a transforming growth factor superfamily protein, a microtubule- associated protein, a serine protease, and/or a coagulation factor.
  • an antibody a tumor- associated antigen, a tissue-specific antigen, an
  • the primary disease-mediating and immune suppressive antigens against which therapeutic antibodies have been developed in oncology include immune checkpoint proteins and cell type specific proteins that are overexpressed by tumor cells [e.g., Epithelial Cell Adhesion Molecule (EPCAM), and Human Epidermal Growth Factor Receptor 2(HER2)], and membranebound cytokines (e.g., CD30).
  • tumor cells e.g., Epithelial Cell Adhesion Molecule (EPCAM), and Human Epidermal Growth Factor Receptor 2(HER2)
  • membranebound cytokines e.g., CD30.
  • a soluble factor comprises a portion or region of a native, membrane-bound molecule, wherein the soluble factor retains an antigenic determinant for which a therapeutic antibody exhibits binding specificity.
  • a therapeutic antibody drug can be leveraged in an extracorporeal device to preemptively remove soluble factors that can interfere with the subsequent intravenous infusion of the therapeutic antibody drug.
  • a soluble factor comprises one of the following antigens or molecules: angiotensin-converting enzyme 2 (ACE2), Programmed Death-Ligand 1 (PD-L1), Programmed Death-Ligand 2 (PD-L2) Programmed Death-1 receptor (PD-1), Cytotoxic T- lymphocyte antigen 4 (CTLA-4), T-cell immunoglobulin and mucin domain-3 (TIM-3), lymphocyteactivation gene 3 (LAG-3), B and T lymphocyte attenuator (BTLA), T cell Immunoglobulin and ITIM domain (TIGIT), Killer-cell Ig-like receptor (KIR), Fas ligand/CD95L, CD96, V-Domain Immunoglobulin Suppressor of T Cell Activation (VISTA), TNF Related Apoptosis Inducing Ligand (TRAIL), CD28, ICOS, CD137 (4-1BB), 0X40, OX40L, CD27, Herpes Virus Entry Mediator (HVEM), DNAM-1,
  • ACE2 angioten
  • methods for enhancing the efficacy of a therapeutic antibody drug comprise (a) identifying a subject in need of treatment with a drug formulation comprising a first therapeutic antibody, wherein the first therapeutic antibody is selected for its binding specificity for an antigen, and wherein the antigen is present in the body as an antigen in a target tissue and as a soluble form of the antigen in blood or plasma; (b) introducing the blood or plasma from the subject into an extracorporeal device comprising a second therapeutic antibody, wherein the second therapeutic antibody is selected for its binding specificity for the soluble form of the antigen in blood or plasma, or portions thereof; (c) contacting the blood or plasma of the subject with the second therapeutic antibody in the extracorporeal device for a time sufficient to allow the soluble form of the antigen, or portions thereof to bind to the second therapeutic antibody; (d) reintroducing
  • Embodiments of the invention provide methods for removing a plurality of soluble factors from the circulatory system of a subject. This objective may be achieved by providing more than one extracorporeal device, wherein each extracorporeal device comprises at least one therapeutic antibody with binding specificity for at least one soluble antigen.
  • an extracorporeal device is provided that is configured to simultaneously clear or reduce the concentrations of a plurality of soluble antigens in blood or plasma of a subject, wherein the extracorporeal device comprises a plurality of therapeutic antibodies with binding specificity for the plurality of soluble antigens present in blood or plasma.
  • Embodiments of the invention may be useful for treating a subject who is undergoing treatment with more than one therapeutic antibody drug.
  • These methods may also be applicable for treating a subject who is receiving a therapeutic antibody drug that has binding specificity for more than one antigen, for example, a bispecific antibody, a trispecific antibody, or other formats described herein, wherein it may be advantageous to clear the plurality of soluble antigens from plasma that could potentially interact with the distinct binding domains of the multispecific therapeutic antibody drug.
  • the methods comprise (a) identifying a subject in need of treatment with a drug formulation comprising a first bispecific therapeutic antibody, wherein the first bispecific therapeutic antibody is selected for its binding specificity for two antigens, and wherein each antigen is present in the body as an antigen in a target tissue and as a soluble form of the antigen in blood or plasma; (b) introducing the blood or plasma from the subject into an extracorporeal device comprising a second bispecific therapeutic antibody, wherein the second bispecific therapeutic antibody is selected for its binding specificity for the soluble forms of the two antigens in blood and plasma, or portions thereof; (c) contacting the blood or plasma of the subject with the second bispecific therapeutic antibody in the extracorporeal device for a time sufficient to allow the soluble forms of the two antigens, or portions thereof to bind to the second bispecific therapeutic antibody; (d) reintroducing the blood or plasma obtained after step (c) into the subject, wherein the blood or plasma obtained after step (c) has a reduced amount of the soluble
  • Another embodiment provides a method for enhancing the activity of a therapeutic antibody drug following administration of at least one dose of the drug to a subject, wherein administration of the drug to the subject elicits a reaction or an immune response that leads to the production of one or more soluble factors, and wherein these soluble factors act as decoys or antagonists of the administered drug and/or subsequent doses of administered drug.
  • circulating entities that may be detected in plasma of a subject post-drug administration include anti-drug antibodies and soluble disease-related antigens expressed on the membranes of extracellular vesicles/exosomes, as well as other entities.
  • the methods comprise (a) identifying a subject in need of treatment with a drug formulation of a first therapeutic antibody, wherein the first therapeutic antibody is selected for its binding specificity for an antigen, and wherein the antigen is present in the body as an antigen in a target tissue and as a soluble form of the antigen in blood or plasma; (b) administering the drug formulation comprising the first therapeutic antibody into the body of the subject, wherein a portion of the administered drug formulation of the first therapeutic antibody is bound to the antigen in the target tissue; (c) introducing the blood or plasma from the subject into an extracorporeal device comprising a second therapeutic antibody, wherein the second therapeutic antibody is selected for its binding specificity for the soluble form of the antigen in blood or plasma, or portions thereof; (d) contacting the blood or plasma from the subject with the second therapeutic antibody in the extracorporeal device for a time sufficient to allow the soluble form of the antigen, or portions thereof to bind to the second therapeutic antibody; (e) reintroducing the blood or plasma obtained after
  • a therapeutic antibody drug acts primarily by binding and blocking interactions between molecules
  • other therapeutic antibody drugs are engineered to activate cytotoxicity or cell lytic pathways via the Fc portion of the antibody.
  • Certain embodiments of the invention provide devices and methods to augment the efficacy of a therapeutic antibody drug by increasing its effector functions at a target site and/or by increasing the availability of a therapeutic antibody drug having these functions.
  • the methods comprise (a) identifying a subject in need of treatment with a drug formulation comprising a first therapeutic antibody, wherein the first therapeutic antibody comprises an antigen-binding domain or region that has binding specificity for an antigen in a target tissue and for a soluble form of the antigen in blood or plasma, and wherein the therapeutic antibody comprises an Fc domain or region that mediates one or more of the following effector functions: antibody-dependent cell cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity; (b) introducing the blood or plasma from the subject into an extracorporeal device comprising a second therapeutic antibody, wherein the second therapeutic antibody comprises an antigen-binding domain or region, and wherein the antigenbinding domain or region of the second therapeutic antibody has binding specificity for the soluble form of the antigen in blood or plasma; (c) contacting the blood or plasma of the subject with the second therapeutic antibody in the extracorporeal device for a time sufficient to allow the soluble form of the antigen, or portions thereof to
  • the methods described herein can be used to improve the safety and/or efficacy of a therapeutic antibody drug as assessed by monitoring of clinical endpoints.
  • clinical safety and efficacy may be determined by one or more of the following standard assessments: monitoring adverse events, overall survival (OS), progression-free survival (PFS), duration of response, objective response rate (ORR), progression-free survival (PFS), as can be determined using RECIST vl.l.
  • the method may involve observing a reduction in disease burden or an improvement in measures of survival in patients treated using the methods disclosed herein as compared to patients that received one or more doses of a therapeutic antibody drug to treat disease without application of methods of this invention.
  • safety and efficacy endpoints will vary according to the disease indication and the therapeutic antibody drug that is used to treat the subject.
  • aspects of the invention also provide devices and methods for treating a subject who is resistant to treatment with a therapeutic antibody drug.
  • Treatment resistance may be broadly defined as a lack of initial response to treatment, or by the eventual failure of a subject to respond to treatment and may be associated with the presence one or more soluble factors present in the blood or plasma of the subject.
  • the method may involve observing a reduction in disease burden or an improvement in measures of survival one or more subjects treated using the methods disclosed herein as compared one or more subjects that received an infusion of a therapeutic antibody without application of methods of this invention.
  • One embodiment of the invention provides devices and methods to improve the therapeutic index of a pharmaceutical composition of a therapeutic antibody drug.
  • the invention provides methods for improving the bioavailability or distribution of a therapeutic antibody drug to the intended tissue site in the body, for example, to a lymph node, into a tumor, or to a molecule or a cell in the blood.
  • the binding of a therapeutic antibody to its intended target tissue in the body is monitored or quantified before, during, or following application of the devices and methods disclosed herein, or at a combination of time points. Studies may be performed to assess the impact of the disclosed methods on the activity of a therapeutic antibody drug, for example, by conducting pharmacodynamic assessments such as receptor occupancy assays.
  • receptor occupancy studies are performed using peripheral blood mononuclear cells from the subject to measure the therapeutic antibody drug that is bound to its intended target, which is expressed as a percentage of occupancy for a given dose of drug or after multiple doses.
  • application of the methods disclosed herein improve the mean peak occupancy and/or the mean plateau occupancy of the intended target antigen by a therapeutic antibody drug; for example, a receptor occupancy of > 70%, > 80%, > 90%, or > 95% may be attained at one hour following drug administration or time points thereafter.
  • Certain embodiments provide devices and methods for modifying the pharmacokinetics of a therapeutic antibody drug by removing one or more soluble factors from blood or plasma. Accordingly, one aspect of the invention involves measuring the quantities of a therapeutic antibody drug following administration of a pharmaceutical composition thereof to a subject, which may be used to infer the impact of one or more soluble factors on the clearance rate of said therapeutic antibody drug in the body.
  • concentrations of a therapeutic antibody drug may be affected by a soluble factor upon initial administration. For example, an intravenously administered drug may be sequestered by a soluble factor in circulation and, as a result, may have an increased rate of clearance from the body.
  • the devices and methods of the invention are applied to increase the detectable concentrations of an intravenously administered therapeutic antibody drug in blood or plasma.
  • appropriate methods can be utilized to quantify the concentrations of a therapeutic antibody in a blood or plasma at one or a series of time points following drug administration.
  • the concentrations of circulating therapeutic antibody can be measured followed by infusion of the drug into a subject and/or following infusion of multiple doses of a therapeutic antibody drug to the subject, for example, after the 1 st infusion, 2 nd infusion, 3 rd infusion, 4 th infusion, or thereafter, in a subject's treatment regimen.
  • Luminex® assays in which a recombinant target antigen is coupled to beads using the xMAP® Antibody Coupling kit (Luminex Corporation, Eindhoven, Netherlands), or similar assays such as enzyme-linked immunosorbent assays (ELISA) for antibody detection.
  • Serum from the subject can be applied to assay plates coated with the relevant target antigen to measure therapeutic antibody concentrations using a standard curve generated using said therapeutic antibody. Serum concentrations of therapeutic antibody can be assessed at different time points following therapeutic antibody drug administration to a subject to assess the kinetics of drug clearance.
  • the concentrations of a therapeutic antibody drug are compared in one or more subjects treated with the extracorporeal treatment methods disclosed herein in comparison to one or more subjects who received the therapeutic antibody drug but did not receive the disclosed methods of treatment.
  • Embodiments of the invention provide methods for selecting a subject for treatment with the devices and methods disclosed herein.
  • a subject is selected who has been prescribed a treatment regimen with a therapeutic antibody drug or who has received at least one dose of a therapeutic antibody drug.
  • Certain embodiments of the invention involve selection of a subject who has already received at least one dose of a therapeutic antibody and/or who may receive additional doses.
  • Certain embodiments of the invention involve selection of a subject who is treatment naive but who is in need of treatment with one or a plurality of doses of a therapeutic antibody.
  • a subject is selected who is at-risk for or predisposed to a disease or condition due to genetic, environmental and/or medical factors or based on biomarker analyses.
  • qualification of a subject for treatment with a particular therapeutic antibody drug as part of a standard of care drug treatment regimen is based on eligibility criteria that are evaluated by a physician, oncologist, or other medical practitioner, and is based on disease type and stage as well as predetermined diagnostic criteria including predictive biomarker tests that are known to one of skill in the art.
  • FDA Food and Drug Administration
  • an immune checkpoint inhibitor such as an anti-PD-1 or an anti-PD-Ll antibody.
  • Non-limiting examples are the Dako IHC 22C3 and 28-8 pharmDx assays (Agilent Technologies, Santa Clara, CA) and the Ventana PD-L1 (SP142) assay (Ventana Medical Systems, Arlington, AZ) used for evaluating PD-L1 expression in tumor tissue.
  • Dako IHC 22C3 and 28-8 pharmDx assays Align Technologies, Santa Clara, CA
  • SP142 Ventana PD-L1
  • Ventana Medical Systems, Arlington, AZ Ventana Medical Systems, Arlington, AZ
  • treatment with pembrolizumab (an anti-PD-1 antibody) or atezolizumab (anti-PD-Ll antibody) in certain tumor types and therapeutic settings is restricted to subjects with tumors that express PD-L1 at levels above specified cut-offs only, using an approved PD-L1 companion diagnostic assay.
  • positivity for the antigen may be scored using tumor tissue specimens that have been stained using immunohistochemistry techniques that are known to one of skill in the art.
  • TPS tumor proportion score
  • TC tumor cell
  • PD-Ll-positive tumor cells are evaluated in relation to all viable tumor cells on the histology slide.
  • IC Immune Cell Score
  • positivity for the biomarker may be defined as PD-L1 expression in >50% of tumor cells (TC) or >10% in tumor-infiltrating immune cells (IC) for treatment of a certain tumor type with a particular immune checkpoint inhibitor drug.
  • positivity for the biomarker may be defined as PD-L1 expression ranging >20%, >30%, or >40% of tumor cells (TC) or >10% in tumor-infiltrating immune cells (IC) for treatment of a tumor with an immune checkpoint inhibitor.
  • companion diagnostic tests performed using tumor tissue may be used to infer the presence of soluble factors comprising said antigens in blood or plasma of a subject, and to indicate the need for treatment with the devices and methods disclosed herein.
  • the invention provides methods of treatment using an extracorporeal device as part of a therapeutic regimen for one or more of the following non-limiting diseases or conditions: a solid tumor, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, cutaneous T cell lymphoma, hairy cell leukemia, multiple myeloma, Hodgkin lymphoma, Non-Hodgkin lymphoma, systemic anaplastic large cell lymphoma, malignant ascites, ankylosing spondylitis, rheumatoid arthritis, atopic dermatitis, ulcerative colitis, myasthenia gravis, Crohn's disease, Alzheimer's disease, type 1 diabetes, multiple sclerosis, hematopoietic stem cell transplant-associated thrombotic microangiopathies, HIV, RSV, COVID-19, Ebola, Anthrax, other viral infections, Castleman disease, psorias
  • cancers whose growth may be inhibited using therapeutic antibody drugs include cancers that are typically responsive to immunotherapy.
  • Non-limiting examples include melanoma (e.g., metastatic malignant melanoma), renal cancer, prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and non-small cell lung cancer.
  • cancers examples include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid
  • Embodiments of the invention provide methods for selecting or identifying a subject to receive therapy with an extracorporeal device by identifying or detecting one or more soluble factors/antigens present in blood or plasma.
  • circulating entities such as extracellular vesicles, exosomes, or microparticles that comprise a soluble antigen are quantified.
  • measurement of baseline (i.e., pre-treatment) levels of a soluble factor in one or more subjects with a disease such as cancer are compared to the levels of the soluble factor in one or more subjects who are symptom-free and/or disease-free, wherein an increased level of soluble factors in the former indicates a need for treatment using the methods disclosed herein.
  • a subject receiving the method is selected as one having an increased amount of a soluble factor in blood or plasma, as compared to a healthy subject or as compared to an earlier measurement in the same subject (for example, at an earlier stage of disease).
  • a subject receiving the method is identified as one who will receive treatment with a pharmaceutical composition of therapeutic antibody drug to which the soluble factor binds.
  • a soluble factor is quantified in blood or a blood component prior to, during, and/or following application of the devices and methods disclosed herein.
  • quantifying a soluble factor may be performed in an isolated serum or plasma specimen from a subject using techniques such as enzyme-linked immunosorbent assay (ELISA) or any equivalent immunoassay for detecting and measuring an antigen.
  • ELISA enzyme-linked immunosorbent assay
  • an antigen may be a component of another entity in plasma, for example, an extracellular vesicle or an exosome.
  • a circulating entity such as an extracellular vesicle or an exosome
  • quantification of an antigen on the extracellular vesicle or exosome using an immunoassay or an equivalent method.
  • methods are provided for evaluating the drug antagonistic effects of a soluble antigen against a therapeutic antibody drug, wherein the therapeutic antibody drug has binding specificity and affinity for the soluble antigen. This information may be used to determine the need for applying the methods of the invention to a subject who is receiving treatment with a therapeutic antibody drug. In other embodiments, these analyses may be used for determining the mechanism of action of a soluble factor and/or the potency of its effects against a therapeutic antibody drug.
  • a plasma specimen may be obtained from a subject to whom a dose of therapeutic antibody drug has been administered; for example, between 1-10 hours after infusion of a dose of drug, and more preferably, between 1-5 hours post drug-administration.
  • the amount of a therapeutic antibody drug that is present in the plasma specimen as well as the amount that is bound to a soluble factor may be quantified using immunoassays, which may be used to determine the percentage of total therapeutic antibody drug that is sequestered in vivo at a particular time point after drug administration.
  • the therapeutic antibody that is bound to an exosome or free in plasma may be quantified using an ELISA or equivalent technique.
  • a cytotoxicity assay may be performed in vitro to determine the extent to which a soluble factor interferes with an effector function of the therapeutic antibody drug.
  • a plasma specimen taken from a subject following administration of a therapeutic antibody drug may be tested for its cytolytic effects against cell line targets in vitro or against autologous tumor cells from the subject ex vivo, if applicable to the drug's mechanism of action. Comparisons of the drug's effector activity may be drawn, for example, between plasma from the subject taken after drug infusion to the same plasma that has been depleted of the soluble factor/exosomes carrying the soluble factor.
  • One object of the invention is to provide a method for reducing the levels of an extracellular vesicle in a subject by extracorporeal circulation of the patient's blood through a cartridge comprising a therapeutic antibody having affinity for an antigen found on the membrane surface of an extracellular vesicle.
  • an extracellular vesicle is an exosome.
  • an exosome expresses an antigen on its membrane surface that is accessible to binding by a therapeutic antibody drug.
  • an exosome expresses an antigen that is capable of intercepting a therapeutic antibody drug away from its intended target antigen in a tissue.
  • performing one or more extracorporeal treatments to bind and trap a soluble antigen that is present on an exosome provides a means for also removing the exosome from plasma. Reducing the exosome concentrations in plasma of a subject may provide additional therapeutic benefits to a subject since exosomes displaying the target antigen likely originate from diseased or disease-affected cells and therefore can harbor diverse protein and nucleic acid cargo that is involved in disease processes in addition to carrying antigens that are decoy the effects of drugs.
  • Embodiments of the invention thereby provide methods to selectively remove drug-binding exosomes from circulation while the remainder of the plasma components, including non-drug binding exosome populations, are returned to the body.
  • the invention provides an extracorporeal method for improving the efficacy of therapeutic antibody drug in a subject by removing extracellular vesicles from blood or plasma, the method comprising (a) identifying a subject in need of treatment with a drug formulation comprising a first therapeutic antibody, wherein the first therapeutic antibody is selected for its binding specificity for an antigen, and wherein the antigen is present in the body as an antigen in a target tissue and as a soluble form of the antigen on a portion of the extracellular vesicles in blood or plasma; (b) introducing the blood or plasma from the subject into an extracorporeal device comprising a second therapeutic antibody, wherein the second therapeutic antibody is selected for its binding specificity for the soluble form of the antigen on extracellular vesicles, or portions thereof; (c) contacting the blood or plasma of the subject with the second therapeutic antibody
  • the concentration of extracellular vesicles or exosomes present in circulation of a subject is determined to provide criteria for applying the devices and methods disclosed herein to a subject.
  • the concentration of a particular soluble factor or antigen on extracellular vesicles or exosomes is determined to provide a basis for performing treatment with an extracorporeal device.
  • the exosomes present in plasma or serum of a subject may first be isolated and quantified using methods known to one of skill in the art. An established protocol for isolation of exosomes includes ultracentrifugation, often in combination with sucrose density gradients, or differential centrifugation.
  • exosome isolation techniques may include size exclusion chromatography, tangential flow filtration, polymer precipitation, antibody-based/immunoaffinity magnetic isolation, and microfluidic devices.
  • the total concentration of exosomes isolated from a blood component of a subject is quantified. Quantification of the exosome concentrations may be performed using known methods, such as nanoparticle tracking analysis (NTA), tunable resistive pulse sensing, flow cytometry, electron microscopy, microfluidic devices, or by quantification of total exosomal protein isolated from a plasma or serum sample from a subject.
  • NTA nanoparticle tracking analysis
  • tunable resistive pulse sensing flow cytometry
  • electron microscopy microfluidic devices
  • quantification of an antigen expressed on the surface of an exosome is performed using a method such as flow cytometry or other techniques for phenotyping vesicles, and preferably, the quantities of an antigen that binds to a therapeutic antibody drug is determined.
  • immune checkpoint inhibitors are designed to augment anti-tumor immunity in a subject by blocking immune inhibitory signaling pathways on immune cells and enhancing T cell anti-tumor responses.
  • An object of the invention is to improve the potency of an immune checkpoint inhibitor drug by reducing the drug antagonistic soluble forms of these molecules that are present in plasma of a subject with cancer.
  • the methods comprise (a) identifying a subject in need of treatment with a drug formulation comprising a first immune checkpoint inhibitor antibody, wherein the first immune checkpoint inhibitor antibody binds to an immune checkpoint protein, and wherein the immune checkpoint protein is present in the body in a target tissue (e.g., on a cell in a lymph node, in blood, or in a tumor) and as a soluble form of the immune checkpoint protein in blood or plasma; (b) introducing the blood or plasma from the subject into an extracorporeal device comprising a second immune checkpoint inhibitor antibody, wherein the second immune checkpoint inhibitor antibody is selected for its binding specificity for the soluble form of the immune checkpoint protein, or portions thereof, in blood or plasma; (c) contacting the blood or plasma of the subject with the second immune checkpoint inhibitor antibody in the extracorporeal device for a time sufficient to allow the soluble form of the immune checkpoint protein, or portions thereof, to bind to the second immune checkpoint inhibitor antibody; (d) reintroducing the blood or plasma
  • Certain embodiments provide methods for treating a subject with an extracorporeal device comprising an anti-PD-Ll therapeutic antibody drug to reduce the concentration of soluble PD-L1 antigen in blood or plasma, wherein the soluble PD-1 antigen comprises PD-L1 carried on extracellular vesicles such as exosomes and/or other soluble forms of PD-L1.
  • the extracorporeal devices disclosed herein may be applied for treating a subject prior to administration of a pharmaceutical composition of an anti-PD-Ll therapeutic antibody.
  • the extracorporeal devices disclosed herein may be applied for treating a subject following administration of a pharmaceutical composition of an anti-PD-Ll antibody.
  • the anti-PD-Ll antibodies in the extracorporeal device and in the pharmaceutical composition have binding specificity for the same or different epitopes of PD-L1.
  • the anti-PD-Ll antibodies in the extracorporeal device and in the pharmaceutical composition comprise one or more of the following: atezolizumab, durvalumab, avelumab, sugemalimab, cosibelimab, portions thereof, or domains thereof.
  • the concentration of soluble PD-L1 in plasma or serum is measured to provide a criterion for selecting a subject to receive treatment with an extracorporeal device, to continue a treatment procedure and/or to indicate the need for additional treatments.
  • the concentration of soluble PD-L1 in plasma or serum is measured both prior to and following treatment with an extracorporeal device.
  • concentration of soluble PD-L1, including PD-L1 antigen carried on extracellular vesicles such as exosomes as well as other entities comprising PD-L1 antigen can be quantified using methods known in the art such as ELISA or other immunoassays that provide quantitative readouts.
  • Embodiments of the invention provide extracorporeal methods for substantially reducing the concentrations of soluble PD-L1 in blood.
  • a pre-treatment concentration of soluble PD-L1 antigen in plasma or serum is >5 pg/mL, >10 pg/mL, > 50 pg/mL, >100 pg/mL, >200 pg/mL, or >500 pg/mL in a subject, where substantial variation in the levels may be expected depending on the type or state of the subject's cancer or another disease that involves PD-L1 upregulation.
  • the concentration of soluble PD-L1 is reduced by at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 90%, or at least 95% in plasma of the subject as compared to pretreatment levels.
  • comparisons may be drawn between the concentration of soluble PD-L1 in a subject with cancer and a disease-free subject as a means for initiating or continuing treatment with an extracorporeal device.
  • one or more subjects with cancer may present with significantly increased concentrations of a soluble factor such as PD-L1 in plasma as compared to the concentrations present in one or more healthy subjects.
  • the concentration of soluble PD-L1 may be normalized or significantly reduced relative to the concentrations in healthy subjects, which can be determined using statistical methods known in the art.
  • a soluble factor comprises a molecule that is involved in modulating aspects of immune function, non-limiting examples of which may include PD-L1, PD-L2, PD-1, CTLA-4, TIM-3, LAG-3, BTLA, CD27, CD80, CD86, TIGIT, CD160, HVEM, Glucocorticoid-induced TNFR-Related protein (GITR), GITR ligand (GITRL), ICOS, 4-1BBL, CD73, B cell Activation Factor (BAFF), APRIL, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, CD137/4-1BB, CD137 ligand/4-IBB ligand, FGL1, CD226, Indole
  • the disclosed methods may be applied for removing soluble forms of these antigens that are found to interfere with the actions of the therapeutic antibody drugs having the complementary antigenic specificity.
  • certain embodiments teach extracorporeal methods for reducing the concentrations of soluble CTLA-4 in a blood component of a subject, wherein a device comprising an anti-CTLA-4 antibody is provided to remove soluble CTLA-4, and wherein soluble CTLA-4 is a decoy or inhibitor of a pharmaceutical composition comprising ipilimumab (an anti-CTLA-4 antibody.
  • the methods can be applied for removal of soluble PD-1, wherein a device comprising an anti-PD-1 antibody is provided to remove soluble PD-1, which is an inhibitor of a pharmaceutical composition comprising pembrolizumab (an anti-PD-1 antibody).
  • a device comprising an anti-PD-1 antibody is provided to remove soluble PD-1, which is an inhibitor of a pharmaceutical composition comprising pembrolizumab (an anti-PD-1 antibody).
  • the methods disclosed herein may be provided to substantially reduce the concentrations of soluble factors that antagonize commercially available drugs that may be directed against one or more of these antigens on a cell or in a tissue such as blood, a lymph node, a tumor, or an organ.
  • Certain embodiments provide methods for treating a subject with an extracorporeal device comprising a therapeutic antibody to reduce the concentration of one or more soluble factors comprising splice variants that are present in plasma.
  • a splice variant may arise via selective splicing of genes and may comprise a secreted form of a receptor or ligand in the circulatory system.
  • the immune checkpoint protein PD-L1 is a transmembrane protein
  • soluble forms of PD-L1 may be present in circulation that comprise splice variants or isoforms of the full-length transmembrane protein.
  • Full-length PD-L1 is a transmembrane protein, which contains 7 coding exons, including a secretory signal at the amino terminus, IgV and IgC domains, a transmembrane domain, a short cytoplasmic tail, and a long 3' untranslated region.
  • splice variants may have various deficiencies or truncations in the IgC domain, absence or substantial truncation of the transmembrane domain, absence of a cytoplasmic domain, and/or may comprise additional amino acids from aberrant splicing in one or more of these domains.
  • an extracorporeal device comprises at least one anti-PD-Ll antibody for removing a soluble PD-L1 splice variant from blood or plasma, wherein the at least one anti-PD-Ll antibody comprises atezolizumab, durvalumab, avelumab, sugemalimab, and/or cosibelimab.
  • the concentration of a soluble factor comprising a splice variant is reduced by at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 90%, or at least 95% in the subject following at least one treatment with an extracorporeal device disclosed herein.
  • the present invention provides methods for reducing the circulating levels of soluble factors that mediate steric disruption to the actions of drugs.
  • methods are provided for binding and removing a soluble factor comprising an anti-drug antibody from blood or plasma using an extracorporeal device disclosed herein.
  • Exposure to a therapeutic antibody drug can evoke an immune response to the drug itself, leading to the formation of antidrug antibodies as well as the release of other soluble factors from diseased cells that act as drug antagonists.
  • Neutralizing anti-drug antibodies may be generated that negate the clinical benefit of the biotherapeutic agent, while non-neutralizing antibodies may also reduce efficacy of the antibody by affecting clearance, pharmacodynamics and/or pharmacokinetics.
  • the immunogenicity of a therapeutic antibody drug that is commercially available will be known in the art and may be reported as the relative incidence of anti-drug antibodies, titers of anti-drug antibodies, and their persistence over time in subjects to whom the drug has been administered. Additionally, the relative impact of anti-drug antibodies on pharmacokinetics, pharmacodynamics, efficacy and safety of the drug may be a component of clinical assessments that are routinely performed in the art. Methods of the invention can therefore be applied for treating a subject who has received a pharmaceutical composition of a therapeutic antibody drug, wherein the therapeutic antibody drug has been determined to be immunogenic based on the titer of anti-drug antibodies that were elicited.
  • anti-drug antibodies are identified and quantified in a sample of plasma obtained from a subject.
  • Measurement of anti-drug antibodies may utilize assays that are designed to detect anti-drug antibodies that specifically bind to a therapeutic antibody and inhibit its pharmacological function.
  • assays are performed to monitor anti-drug antibodies that eliminate the therapeutic antibody from the body, or both. Assays can be performed to assess antibodies of all isotypes, including low- and high-affinity anti-drug antibodies.
  • screening test methods are performed to detect anti-drug antibodies following administration of a therapeutic antibody drug to the subject, for example, using enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA) methods, surface plasmon resonance (SPR), bio-layer interferometry (BLI), high-pressure liquid chromatography (HPLC)-based methods, or immunoassays.
  • ELISA enzyme-linked immunosorbent assay
  • ELIA electrochemiluminescence immunoassay
  • SPR surface plasmon resonance
  • BLI bio-layer interferometry
  • HPLC high-pressure liquid chromatography
  • an immunoassay or equivalent method can be performed to evaluate the level of the therapeutic antibody drug concomitant with the level of an anti-drug antibody. This assessment may be used to determine the impact of the disclosed methods for removing anti-drug antibodies on the clearance of the therapeutic antibody drug from the body, which may be compared to known pharmacokinetics for the therapeutic antibody drug administered in the absence of the disclosed devices and methods. Certain embodiments also involve monitoring adverse events and efficacy endpoints for the therapeutic antibody drug when administered alone or in combination with the disclosed devices and methods.
  • Certain embodiments provide a method for targeting anti-drug antibodies in a subject who has received at least one dose of an immunogenic therapeutic antibody drug, wherein the method comprises delivering one or more treatments with an extracorporeal device, wherein the extracorporeal device comprises a therapeutic antibody that binds to removes an anti-drug antibody from blood or plasma.
  • the concentration of an anti-drug antibody is reduced by at least at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 90%, or at least 95% in the subject following at least one treatment with an extracorporeal device disclosed herein.
  • the disclosed methods are useful for improving the safety and/or efficacy of a therapeutic antibody drug, which may permit the initial or continued administration of one or more dose(s) of a therapeutic antibody drug to a subject that would otherwise be precluded or discontinued due to the drug's inherent immunogenicity.
  • Another aspect of the invention provides methods for harvesting disease-related biomarkers from the circulatory system of a subject.
  • prognostic and diagnostic biomarkers can be identified and quantified by assessment of the types of soluble factors, their abundance, and the additional antigenic content that may be captured and removed during an extracorporeal procedure using the devices disclosed herein.
  • certain embodiments disclose recovering the substrate from the used cartridge, wherein the substrate comprises an immobilized therapeutic antibody as a ligand that has contacted plasma containing one or a plurality of soluble factors.
  • a cartridge may have a port (e.g., a side port) from which the substrate or a portion thereof can be recovered from a used cartridge.
  • an elution procedure is performed to recover the bound soluble factors by dissociation from the therapeutic antibody ligand in a cartridge that has contacted plasma.
  • dissociation interactions or bonds between therapeutic antibody and the soluble factor(s) are disrupted using methods known to one of ordinary skill in the art.
  • the specific protocol for dissociating the soluble factors may be affected by the specific type of soluble factor that is recovered, as well as the composition of its antigenic moieties.
  • reagents or chemicals that may be useful for eluting a bound soluble factor include a low pH solution (for example, a solution between pH 1.5 to 2.8), or a chaotropic agent (for example, a solution comprising guanidine hydrochloride).
  • competitive binding can be used to dissociate bound soluble factors by addition of competitive receptors or ligands to the substrate.
  • dissociation of antigen-antibody binding may not be required and, alternatively, the recovered substrate may be assayed directly for the presence and quantity of a soluble factor. Subsequently, methods known in the art may be applied for quantifying a bound soluble factor.
  • Embodiments of the invention include characterization of the soluble factors eluted or recovered from a cartridge following an extracorporeal procedure, for example, using ELISA, MSD assays, lateral flow immunoassays, Western blotting, mass spectrometry, MALDI-TOF, nanoparticle tracking analysis (NTA), tunable resistive pulse sensing, flow cytometry, and equivalent methods.
  • the type and quantity of soluble factors eluted from a used cartridge can serve as a biomarker for the subject's disease status or prognosis.
  • the presence and quantity of a soluble factor eluted from a used cartridge following an extracorporeal procedure is monitored to assess the performance of the cartridge for its intended use.
  • the methods further comprise determining the efficiency of capture of a soluble factor by an extracorporeal device disclosed herein.
  • laboratory testing is performed wherein a solution (e.g., phosphate buffered saline) or a blood component (e.g., plasma) is circulated through an extracorporeal device or a scaled-down laboratory version thereof having the same internal components to quantify the removal of a soluble factor.
  • a soluble factor which may comprise a recombinant protein or an isolated soluble factor or vesicle from in vitro culture or from isolated from body fluid of a mammal), can be spiked into the solution comprising a buffer or a blood component at a known concentration.
  • a specimen derived from a subject, wherein endogenous concentrations of a soluble factor are verified to be present, may be used in laboratory testing to assess the performance of an extracorporeal device.
  • a representative ex vivo system for evaluating the performance of an extracorporeal device may include a pump for driving the flow of the solution or specimen through the inlet of a device, through the compartment or chamber, and through the outlet.
  • the bench-top extracorporeal circuit may be run for a predetermined length of time (for example, for at least 15 min, 30 min, 1 hour, 2 hours, 3 hours, or longer).
  • a pump may comprise a peristaltic pump, a syringe pump, a piston pump, and/other pumps, which control the flow rate of solution through the device.
  • the concentration of a soluble factor remaining in solution following performance of the laboratory procedure is assessed relative to its concentration in the starting solution, which may be calculated as the percentage of soluble factor removed by the extracorporeal device at the end of the procedure.
  • the percent of a soluble factor removed by the extracorporeal device is at least at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 90%, or at least 95%, or more.
  • the capture efficiency can be determined as a function of procedural time, wherein the concentration of the soluble factor in the inflow solution and the concentration of the soluble factor in the outflow solution is monitored at one or more time points during operation of the device, and these values are expressed as the percentage of removal of the soluble factor. Capture efficiency measurements may be taken at various time points during the procedure, for example, over the first 5, 10, 15, 30, 45, 60, 90, 120 or more minutes of a procedure, to determine whether binding saturation occurs as more soluble factors are cumulatively retained within the substrate of the cartridge. In certain embodiments, the capture efficiency of the soluble factor is at least 40%, at least 50%, at least 70%, at least 80%, at least 90%, or more. Without being bound by theory, the capture efficiency may be affected by factors including the volume/concentration of the substrate in the cartridge, the concentration of therapeutic antibody in the substrate, the cartridge size and dimensions, and the flow rate of the solution or blood component through the cartridge.
  • another object of the invention relates to monitoring and quantifying the removal of a soluble factor from plasma during an extracorporeal procedure performed in a subject using the abovementioned methods and calculations for determining the concentration of a soluble factor and capture efficiency of an extracorporeal device.
  • an apheresis procedure is performed using an extracorporeal device disclosed herein, wherein the apheresis procedures reduces levels of a soluble factor in plasma by at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 90%, or at least 95% or more, by the end of the procedure.
  • the capture efficiency of the soluble factor is at least 40%, at least 50%, at least 70%, at least 80%, at least 90%, or more at time points during the extracorporeal procedure.
  • Specific aspects of the invention provide a method for treating a subject with a tumor, the method comprising (a) Selecting a subject who has been prescribed one or more doses of a therapeutic antibody drug to treat a tumor, wherein the therapeutic antibody drug has binding specificity for an antigen in a target tissue or site; b) Performing one or more extracorporeal procedures using a device comprising an immobilized therapeutic antibody as an affinity capture agent for removal of a soluble factor from blood or plasma of the subject, wherein the soluble factor comprises the antigen; and (c) Administering the therapeutic antibody drug into the subject for treating the tumor.
  • Methods of the invention are provided to substantially reduce the concentrations of a soluble factor, thereby permitting increased delivery of a therapeutic antibody drug to a target tissue or site, such as blood, a lymph node, or a tumor, which corresponds to the site where the target antigen is expressed.
  • a target tissue or site such as blood, a lymph node, or a tumor, which corresponds to the site where the target antigen is expressed.
  • the methods described herein are useful for improving the clinical safety and/or efficacy of the therapeutic antibody drug for treating the tumor, as may be determined by one or more assessments: monitoring of adverse events, overall survival (OS), progression-free survival (PFS), duration of response, and overall response rate (ORR), wherein comparisons can be drawn by comparing one or more subjects that received the therapeutic antibody drug alone to one or more subjects that also received at least one treatment with an extracorporeal device.
  • OS overall survival
  • PFS progression-free survival
  • ORR overall response rate
  • an extracorporeal device is applied for removal of a soluble factor in a subject who has been identified as a clinical non-responder to an anti-drug antibody, as defined based on a failure to achieve an objective response by RECIST criteria (Response evaluation criteria in solid tumors) and, preferably, after a course of therapy with an anti-drug antibody spanning weeks or months.
  • RECIST criteria Response evaluation criteria in solid tumors
  • a subject with cancer is identified who meets the eligibility criteria for receiving treatment with an immune checkpoint inhibitor, for example, the anti-PD-Ll antibody atezolizumab.
  • a treatment regimen of the present invention may include the following steps: (a) providing an extracorporeal device comprising atezolizumab; (b) removing a blood component (e.g., plasma) from the subject, the blood component having a concentration of PD-L1; (c) processing the blood component using the extracorporeal device comprising atezolizumab, wherein atezolizumab is in contact with soluble PD-L1 in the blood component; (d) binding of at least a portion of the soluble PD-L1 from the blood component to atezolizumab; (e) reintroducing the blood component without said portion of soluble PD-L1 back to the subject; and (f) Performing an intravenous infusion of a pharmaceutical formulation of atezolizumab into the subject for treating the tumor.
  • a blood component e.g
  • Atezolizumab may be administered to a subject at any time following completion of steps (a-e), once a portion of the soluble PD-L1 has been removed from the blood component.
  • atezolizumab is generally administered at a specified dose, for example, 1,200 mg as an intravenous infusion over 30-60 min every 3 weeks.
  • the methods of the invention may be performed, for example, by administering between 1 and 5 extracorporeal procedures prior to infusion of the first dose of atezolizumab, and before subsequent doses in successive treatment cycles of the patient with the drug.
  • the methods of the invention may be carried out daily, every two days, or three times weekly, for example, prior to each infusion of atezolizumab.
  • the reduction of soluble PD-L1 from a patient's blood or a blood component is measured by obtaining a blood specimen priorto and after performing the disclosed methods, as a means for determining whether the procedures should be repeated to achieve a desired reduction in the levels of one or more soluble factors.
  • the soluble PD-L1 concentration in blood of a subject is reduced by at least at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 90%, or at least 95% by a single treatment using the devices and methods disclosed herein.
  • a reduction of soluble PD-L1 concentration in blood of a subject of at least at least 20%, at least 30%, at least 50%, at least 75%, at least 80%, at least 90%, or at least 95% is used to indicate efficient performance of an extracorporeal device and/or sufficient removal of soluble PD-L1 from the subject, such that the step of administering the pharmaceutical formulation of atezolizumab can proceed.
  • the extent of reduction of soluble PD-L1 may take into consideration a time-based component, i.e., the longer the treatment time, the more soluble PD-L1 will be removed.
  • the treatment procedure can be adjusted accordingly, for example, by treating between 1.5 and 5 plasma volumes (PV) of a subject using an extracorporeal device disclosed herein that is operated using an apheresis machine.

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Abstract

La présente invention concerne des procédés, des dispositifs et des kits pour améliorer l'activité et l'administration d'un médicament anticorps thérapeutique chez un sujet par suppression ou élimination de facteurs solubles qui sont des antagonistes ou des leurres de médicament du système circulatoire. L'invention concerne des procédés extracorporels qui peuvent être déployés en tant que partie de régimes de traitement avec une administration de médicament anticorps thérapeutique à un sujet. Certains modes de réalisation comprennent un double mode d'exposition d'anticorps thérapeutique, le sang ou un composant sanguin étant traité avec un anticorps thérapeutique dans un dispositif extracorporel avant ou après l'administration d'une composition pharmaceutique d'un médicament d'anticorps thérapeutique à un sujet pour le traitement d'une maladie.
PCT/US2024/028579 2023-05-10 2024-05-09 Dispositifs pour améliorer l'activité d'anticorps thérapeutiques Pending WO2024233781A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090156976A1 (en) * 2007-03-01 2009-06-18 Martin Korbling Devices and Methods for Extracorporeal Ablation of Circulating Cells
US20180223255A1 (en) * 2015-10-08 2018-08-09 Innovative Cellular Therapeutics CO., LTD. Activation and Expansion of T Cells
US20210046119A1 (en) * 2018-04-20 2021-02-18 Children's National Medical Center Fixed ratio ex vivo activated mixed lymphocyte products for use in the treatment of cancer
US20210115378A1 (en) * 2018-05-09 2021-04-22 Yale University Compositions and systems for ex vivo cell modulation and methods of use thereof
US20220064584A1 (en) * 2014-10-31 2022-03-03 Massachusetts Institute Of Technology Delivery of biomolecules to immune cells

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090156976A1 (en) * 2007-03-01 2009-06-18 Martin Korbling Devices and Methods for Extracorporeal Ablation of Circulating Cells
US20220064584A1 (en) * 2014-10-31 2022-03-03 Massachusetts Institute Of Technology Delivery of biomolecules to immune cells
US20180223255A1 (en) * 2015-10-08 2018-08-09 Innovative Cellular Therapeutics CO., LTD. Activation and Expansion of T Cells
US20210046119A1 (en) * 2018-04-20 2021-02-18 Children's National Medical Center Fixed ratio ex vivo activated mixed lymphocyte products for use in the treatment of cancer
US20210115378A1 (en) * 2018-05-09 2021-04-22 Yale University Compositions and systems for ex vivo cell modulation and methods of use thereof

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