Extracorporeal removal of microvesicular particles
Inventors
Ichim, Thomas • Tullis, Richard H.
Assignees
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Publication Number
US-9707333-B2
Publication Date
2017-07-18
Expiration Date
Abstract
The invention described herein teaches methods of removing microvesicular particles, which include but are not limited to exosomes, from the systemic circulation of a subject in need thereof with the goal of reversing antigen-specific and antigen-nonspecific immune suppression. Said microvesicular particles could be generated by host cells that have been reprogrammed by neoplastic tissue, or the neoplastic tissue itself. Compositions of matter, medical devices, and novel utilities of existing medical devices are disclosed.
Core Innovation
The invention relates to extracorporeal removal of circulating exosomes that comprise an MHC-I antigen or an MHC-II antigen. Circulating tumor-associated microvesicles/exosomes are described as inducing immune suppression, including T cell apoptosis and mechanisms involving TCR-zeta chain cleavage and FasL, together with MHC-related antigen presentation features such as MHC I-peptide complexes and MHC II-peptide complexes.
The described approach captures the antigen-bearing exosomes by contacting whole blood, plasma, or serum with a substrate that comprises an antibody specific for an MHC-I antigen or an MHC-II antigen, such that exosomes comprising the MHC-I antigen or MHC-II antigen are captured on the substrate. Patient selection is described based on benefit from capture/removal, and in other embodiments on having a greater exosomal content compared to a healthy person.
The document further describes extracorporeal device concepts for capturing exosomes, including closed extracorporeal circuits using affinity adsorbents and hollow-fiber plasma separators with immobilized capture agents. Immobilized antibody/lectin capture on a porous hollow-fiber exterior is described in connection with allowing blood cells to pass through a filter interior while exosomes diffuse to the porous exterior, followed by reinfusion after clearance and monitoring of exosome burden and immune responses such as IFN-gamma.
Claims Coverage
The independent claims cover capturing MHC-I antigen- or MHC-II antigen–comprising exosomes using an antibody-specific substrate, with patient selection criteria, and return of treated blood/plasma/serum with substantially fewer antigen-bearing exosomes. The inventive features center on antigen-directed exosome capture and selection/handling criteria that reduce the patient’s exosome content.
Antibody-specific substrate capturing MHC-I or MHC-II exosomes
Selecting a patient suspected of receiving a benefit from the capture and removal of exosomes, contacting whole blood, plasma, or serum from said selected patient with a substrate that comprises an antibody that is specific for an MHC-I antigen or an MHC-II antigen, and capturing the exosomes that comprise the MHC-I antigen or the MHC-II antigen on the substrate.
Patient selection by elevated exosomal content and return with reduced exosomes
Selecting a patient that has a greater exosomal content compared to a healthy person, contacting whole blood, plasma, or serum from said selected patient with a substrate that comprises an antibody that is specific for an MHC-I antigen or an MHC-II antigen with exosomes that comprise the MHC-I antigen or the MHC-II antigen obtained from said patient, and returning contacted whole blood, plasma, or serum to the patient wherein said contacted whole blood, plasma, or serum contains substantially fewer exosomes comprising MHC-I antigen or MHC-II antigen in comparison to whole blood, plasma, or serum originally residing in the patient.
Overall, the claims cover exosome capture directed to MHC-I or MHC-II antigens using an antibody-specific substrate, with one independent claim emphasizing suspected benefit from capture/removal, and another emphasizing selection by elevated exosomal content followed by return of treated whole blood/plasma/serum with substantially fewer antigen-bearing exosomes.
Stated Advantages
Reverse immune suppression by removing circulating exosomes/microvesicles that induce immune suppression, including mechanisms such as T cell apoptosis and associated antigen-related pathways.
Enhance antitumor immunity by de-repressing Th1/T cell function and enabling an antitumor immune response.
Provide a method that results in contacted whole blood, plasma, or serum containing substantially fewer exosomes comprising MHC-I antigen or MHC-II antigen compared to the patient’s original content.
Documented Applications
Use for monitoring exosome burden, including FasL and/or MHC-related measures, and immune response, including IFN-gamma response, followed by reinfusion after exosome clearance.
Therapeutic use in combination with a cancer vaccine, immune stimulants, or chemotherapy, as part of reversing immune suppression and enhancing antitumor immunity.
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