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WO2016028879A1 - Compositions et procédés pour moduler une réponse immunitaire - Google Patents

Compositions et procédés pour moduler une réponse immunitaire Download PDF

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Publication number
WO2016028879A1
WO2016028879A1 PCT/US2015/045868 US2015045868W WO2016028879A1 WO 2016028879 A1 WO2016028879 A1 WO 2016028879A1 US 2015045868 W US2015045868 W US 2015045868W WO 2016028879 A1 WO2016028879 A1 WO 2016028879A1
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WO
WIPO (PCT)
Prior art keywords
cells
disease
subject
enzyme
protein
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2015/045868
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English (en)
Inventor
Valder R. Arruda
Michael C. MILONE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Childrens Hospital of Philadelphia CHOP
University of Pennsylvania Penn
Original Assignee
Childrens Hospital of Philadelphia CHOP
University of Pennsylvania Penn
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Childrens Hospital of Philadelphia CHOP, University of Pennsylvania Penn filed Critical Childrens Hospital of Philadelphia CHOP
Publication of WO2016028879A1 publication Critical patent/WO2016028879A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • 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
    • C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/12—Animals modified by administration of exogenous cells
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/106—Primate
    • 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

  • the present invention relates to the fields of immunology. More specifically, the invention provides compositions and methods for the modulation of the immune response, particularly during enzyme replacement therapy.
  • ERT enzyme/protein replacement therapy
  • IgG inhibitory antibodies
  • hemophilia is an X-linked recessive bleeding disorder resulting from deficiency of FVIII or FIX due to mutations in the respective genes.
  • FVIIa plasma-derived or recombinant FVIII or FIX and eventually activated FVII
  • ITI immune tolerance induction
  • methods for increasing the amount or activity of an enzyme or a protein in a subject are provided, particularly where the subject is deficient (e.g., less activity or amount than in a normal or healthy subject) or lacks the enzyme or protein.
  • methods of treating and/or inhibiting a disease or disorder characterized by a deficient or absent enzyme or protein are provided.
  • the disease or disorder is characterized by neutralizing or inhibitory antibodies to the enzyme or protein.
  • the instant invention also encompasses methods for increasing the efficacy of an enzyme replacement therapy.
  • the methods of the invention comprise administering to a subject T cells comprising a chimeric antigen receptor immunologically specific for CD 19, wherein the subject is undergoing and/or has undergone enzyme replacement therapy.
  • the T cells are autologous to the subject.
  • the T cells may be treated ex vivo.
  • the disease or disorder being treated by enzyme replacement therapy is selected from the group consisting of hemophilia, lysosomal storage disease, neuronal ceroid lipofuscinoses, urea cycle disorder, adenosine deaminase deficiency, and hyperammonemia.
  • CAR chimeric antigen receptor
  • CAR-modified T cells The depletion of B cells targeting CD 19 caused by the use of chimeric antigen receptor (CAR)-modified T cells also affects memory B cells and plasmocytoid cells that perpetuate the subject's ability to secrete antibodies to the therapeutic protein. Therefore, the use of the CAR-modified T cell therapy facilitates the eradication of inhibitory antibodies to therapeutic proteins. Additionally, the methods of the instant invention will inhibit and/or prevent the recurrence of antibodies upon re-exposure to an antigen (e.g., the therapeutic protein/enzyme).
  • an antigen e.g., the therapeutic protein/enzyme
  • B-cells not only produce the inhibitors, but also serve as antigen presenting cells (APCs) to FVIII specific T-cells.
  • APCs antigen presenting cells
  • This dual role of B-cells essentially serves as a feed-forward mechanism that can exacerbate the immune response to FVIII.
  • Direct targeting of memory B-cells has been approached in an in vitro model for FVIII inhibitor responses (Hausl et al. (2004) Blood 104: 1 15-22).
  • the T cell initiates the formation of antibodies and B cells perpetuate the ability to keep generating antibodies when reencountering the antigen (e.g., FVIII or FIX in the case of hemophilia).
  • the methods of the instant invention will result in the development of T cells specific for CD 19.
  • CD 19 is the hallmark differentiation antigen of the B cell lineage and is crucial for both initial B cell activation by T- dependent antigens and the maturation and selection of the activated cells into the memory B cell compartment.
  • CAR autologous modified T cells expressing chimeric antigen receptor
  • the instant invention provides methods of treating other diseases or disorders (e.g., non-cancerous or non-malignant diseases) characterized or complicated by the formation of antibodies to ERT by using CAR- 19 technology.
  • the prototypical CAR technology is the use of a single chain Fv region of a monoclonal antibody to recognize a cell-surface antigen independent of the major histocompatibility complex (MHC) coupled with one or more signaling molecules to activate genetically modified T cells for killing, proliferation, and cytokine production.
  • MHC major histocompatibility complex
  • modified T cells required to inhibit B cells in the patients of the instant invention will be likely be lower than that already tested in humans with B cell malignancies because normal B cells constitute only -10% of hematopoietic system compartment.
  • myeloid ablative or myelosuppressive drugs used to create a space in the bone marrow for T cell engraftment and long-term expression, are optional with the instant invention.
  • transient and/or mild bone marrow conditioning or ablation is used, particularly drug-induced. For the reasons set forth above, even a transient depletion of B cells will be effective (if not, in fact, desirable) for the instant invention. Accordingly, non-integrating vectors and/or RNAi may be used with the CAR technology in the instant invention.
  • IVIG intravenous immunoglobulin
  • the disease or disorder can be treated with enzyme/protein replacement therapy.
  • the disease or disorder is not a malignancy or cancer.
  • the disease or disorder is not a B cell malignancy or cancer.
  • Diseases and disorders that can be treated by enzyme/protein replacement therapy include, without limitation, hemophilia (hemophilia A or B), lysosomal storage diseases (LSD), urea cycle disorder, adenosine deaminase deficiency, neuronal ceroid
  • NCL lipofuscinoses
  • lysosomal storage diseases include, without limitation, glycogen storage disease (e.g., type II (Pompe disease)), Gaucher's disease, Niemann-Pick disease, Fabry's disease, and mucopolysaccharidosis (e.g., MPS I, MPS II, MPS VI, etc.).
  • enzyme replacement therapy encompasses the delivery of a protein without enzymatic activity or an enzyme. Further, enzyme replacement therapy encompasses the administration of the protein/enzyme to the subject as well as gene therapy wherein a nucleic acid molecule encoding the protein/enzyme is delivered to the subject for expressing the protein/enzyme.
  • the methods of the instant invention comprise administering a nucleic acid (DNA or RNA) encoding CAR- 19 (chimeric antigen receptor to CD 19) to the subject.
  • the method comprises administering T cells (e.g., T cell, cytotoxic T cell, and/or natural killer) comprising nucleic acid encoding CAR- 19 to the subject.
  • T cells e.g., T cell, cytotoxic T cell, and/or natural killer
  • the T cells may be autologous.
  • the methods may comprise transducing T cells ex vivo with a nucleic acid encoding a chimeric antigen receptor of the instant invention (e.g., an integrating or non- integrating vector for the expression of the chimeric antigen receptor).
  • the methods of the instant invention may further comprise obtaining the T cells from the subject.
  • the nucleic acid encoding CAR- 19 (chimeric antigen receptor to CD 19) and/or T cells comprising the nucleic acid encoding CAR- 19 may be administered to a subject before, during, and/or simultaneously with an enzyme/protein replacement therapy.
  • the CAR-19 therapy of the instant invention may be administered before (e.g., 1, 2, 3, 4, or, 5 days or more) prior to beginning enzyme/protein replacement therapy.
  • the CAR-19 therapy may be administered before, during, and/or simultaneously with any administration (e.g., initial and/or booster) of enzyme replacement therapy.
  • the chimeric antigen receptor of the instant invention comprises an ectodomain
  • the ectodomain of the chimeric antigen receptor of the instant invention comprises an antibody or fragment thereof (an antigen-binding fragment thereof) which is immunologically specific for CD 19 (e.g., Cluster of Differentiation 19; Gene ID: 930; UniProtKB/Swiss-Prot: P15391.6; and GenBank Accession No. P15391 provide amino acid and nucleotide sequences for human CD 19).
  • the antibody or fragment thereof comprises a Fab or a scFv, particularly scFv.
  • the antibody or an antigen-binding fragment of the ectodomain may be linked to the transmembrane domain via an amino acid linker/spacer (e.g., about 1 to about 100 amino acids).
  • the ectodomain may also comprise a signal peptide (e.g., an endoplasmic reticulum signal peptide).
  • the transmembrane domain of the chimeric antigen receptor of the instant invention may be any transmembrane domain.
  • the transmembrane domain is a hydrophobic alpha helix that spans the cell membrane.
  • the transmembrane domain is from the same protein as the endodomain.
  • transmembrane domains include, without limitation, transmembrane domains from T-cell receptor (TCR), CD28, CD3, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.
  • TCR T-cell receptor
  • CD28 CD3, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.
  • CD3 ⁇ or CD28 is from CD3 ⁇ or CD28.
  • the endodomain of the chimeric antigen receptor of the instant invention comprises at least one signaling domain (e.g., a signaling domain comprising one or more immunoreceptor tyrosine-based activation motifs (ITAMs)).
  • the signaling domain is activated by antigen binding to the ectodomain and leads to the activation of the T cells.
  • Signaling domains include, without limitation, the signaling domain (e.g.,
  • the endodomain comprises the cytoplasmic domain or fragment thereof of CD3-s, CD3-Y, or CDS- ⁇ chain.
  • the endodomain comprises the signaling domains of ⁇ 3- ⁇ , CD28, 4-1BB, and/or OX40.
  • the endodomain comprises the signaling domains of CDS- ⁇ , CD28, and OX40.
  • the endodomain comprises the 4- I BB signaling domain.
  • Nucleic acid molecules encoding the chimeric antigen receptor of the instant invention may be contained within a vector (e.g., operably linked to a promoter and/or enhancer for expression in the desired cell type).
  • the vector may be DNA or RNA.
  • the vector may be an integrating vector or a non-integrating vector. Examples of vectors include, without limitation, plasmids, phagemids, cosmids, and viral vectors. In a particular embodiment, the vector is a viral vector.
  • viral vectors include, without limitation: a parvoviral vector, lentiviral vector (e.g., HIV, SIV, FIV, EIAV, Visna), adenoviral vector, adeno-associated viral vector (e.g., AAV1 -9), herpes vector (HSVl-8), or a retroviral vector.
  • the viral vector may be a psuedotype viral vector.
  • the vector may be a SIV or HIV based, VS VG pseudo-typed lentiviral vector.
  • the promoter of the vector may be constitutive or inducible.
  • promoters include, without limitation: the immediate early cytomegalovirus (CMV) promoter, elongation growth factor- la, simian virus 40 (SV40) early promoter, mouse mammary tumor virus (MMTV), human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, actin promoter, myosin promoter, hemoglobin promoter, creatine kinase promoter, metallothionine promoter, glucocorticoid promoter, progesterone promoter, and tetracycline promoter.
  • CMV immediate early cytomegalovirus
  • SV40 simian virus 40
  • MMTV mouse mammary tumor virus
  • HSV human immunodeficiency virus
  • LTR long terminal repeat
  • MoMuLV promoter MoMuLV promoter
  • the nucleic acid molecules (e.g., vectors) of the instant invention may be transferred into the desired target cell (e.g., T cell) by any physical, chemical, or biological means.
  • Methods for transferring nucleic acid molecules into cells are well known in the art (see, e.g., Sambrook et al. (Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York).
  • Exemplary methods of transferring the nucleic acid molecules into cells include, without limitation: calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, infection (e.g., with viral vector), and colloidal dispersion systems (e.g., nanocapsules, microspheres, micelles, and liposomes).
  • the instant invention also encompasses methods of treating, inhibiting, and/or preventing an autoimmune disease comprising the administration of the CAR-19 therapy of the instant invention to a subject in need thereof (e.g., one with an autoimmune disease).
  • an autoimmune disease refers to a disorder that results from an inappropriate and excessive immune response to a self-antigen.
  • autoimmune diseases include but are not limited to, Addision's disease, alopecia greata, ankylosing spondylitis, autoimmune hepatitis, autoimmune parotitis, Crohn's disease, diabetes (Type I), dystrophic epidermolysis bullosa, epididymitis, glomerulonephritis, Graves' disease, Guillain-Barr syndrome, Hashimoto's disease, hemolytic anemia, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, spondyloarthropathies, thyroiditis, vasculitis, vitiligo, myxedema, pernicious anemia, ulcerative colitis, thrombocytic thrombocytopenic purpur
  • the cells or nucleic acid molecules (e.g., vector, particularly viral vectors (e.g., as in gene therapy) of the instant invention may be administered to a patient in a composition further comprising a pharmaceutically acceptable carrier.
  • the composition is administered via intravenous injection.
  • the cells or nucleic acid molecules of the instant invention (CAR-19 therapy) may be administered alone or in combination with other agents known to treat, inhibit, and/or prevent the disease being treated.
  • the CAR-19 therapy may be administered concurrently and/or consecutively with the other therapeutic agents.
  • Kits comprising at least one first composition comprising at least one CAR-19 therapy of the instant invention (e.g., nucleic acids) and at least one second composition comprising at least one other therapeutic agent are also encompassed by the instant invention.
  • compositions in which to deliver the cells or nucleic acid molecules of the instant invention may be determined by a medical practitioner upon consideration of a variety of physiological variables, including, but not limited to, the patient's condition and hemodynamic state.
  • a variety of compositions well suited for different applications and routes of administration are well known in the art and are described hereinbelow.
  • the preparation containing the cells or nucleic acid molecules of the instant invention may contain a physiologically acceptable matrix and may be formulated as a pharmaceutical preparation.
  • the preparation can be formulated using substantially known prior art methods, it can be mixed with a buffer containing salts, such as NaCl, CaCl 2 , and amino acids, such as glycine and/or lysine, and in a pH range from 6 to 8.
  • the purified preparation containing the cells or nucleic acid molecules can be stored in the form of a finished solution or in lyophilized or deep-frozen form.
  • the preparation is stored in lyophilized form and is dissolved into a visually clear solution using an appropriate reconstitution solution.
  • the preparation according to the present invention can also be made available as a liquid preparation or as a liquid that is deep-frozen.
  • the preparation according to the present invention is especially stable, i.e., it can be allowed to stand in dissolved form for a prolonged time prior to application.
  • compositions suitable for use in the invention include
  • compositions wherein the active ingredients are contained in an effective amount to achieve the intended therapeutic purpose Determining a therapeutically effective dose is well within the capability of a skilled medical practitioner using the techniques and guidance provided in the present invention. Therapeutic doses will depend on, among other factors, the age and general condition of the subject, the severity of the aberrant blood coagulation phenotype, and the strength of the control sequences regulating the expression levels of the peptide. Thus, a therapeutically effective amount in humans will fall in a relatively broad range that may be determined by a medical practitioner based on the response of an individual patient to peptide treatment.
  • Direct delivery of the pharmaceutical compositions in vivo may generally be accomplished via injection using a conventional syringe.
  • the compositions of the instant invention may be delivered subcutaneously, epidermally, intradermally, intrathecally, intraorbitally, intramucosally, intraperitoneally, intravenously, intraarterially, orally, intrahepatically or intramuscularly.
  • a clinician specializing in the treatment of patients with blood coagulation disorders may determine the optimal route for administration of the compositions of the instant invention based on a number of criteria, including, but not limited to: the condition of the patient and the purpose of the treatment.
  • the terms "host,” “subject,” and “patient” refer to any animal, particularly mammals including humans.
  • “Pharmaceutically acceptable” indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • a “carrier” refers to, for example, a diluent, adjuvant, preservative (e.g.,
  • Benzyl alcohol e.g., ascorbic acid, sodium metabisulfite
  • solubilizer e.g., Tween 80, Polysorbate 80
  • emulsifier e.g., Tris HC1, acetate, phosphate
  • buffer e.g., Tris HC1, acetate, phosphate
  • antimicrobial e.g., bulking substance
  • excipient e.g., lactose, mannitol
  • auxiliary agent or vehicle e.g., auxiliary agent or vehicle with which an active agent of the present invention is administered.
  • Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions may be employed as carriers, particularly for injectable solutions.
  • Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin (Mack Publishing Co., Easton, PA); Gennaro, A. R., Remington: The Science and Practice of Pharmacy, (Lippincott, Williams and Wilkins); Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y.; and Kibbe, et al., Eds., Handbook of Pharmaceutical
  • treat refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the condition, etc.
  • the term "prevent” refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., generation of inhibitors) resulting in a decrease in the probability that the subject will develop the condition.
  • a “therapeutically effective amount” of a compound or a pharmaceutical composition refers to an amount effective to prevent, inhibit, or treat a particular disorder or disease and/or the symptoms thereof.
  • antibody or “antibody molecule” is any immunoglobulin, including antibodies and fragments thereof, that binds to a specific antigen.
  • antibody or antibody molecule contemplates intact immunoglobulin molecules, immunologically active portions of an immunoglobulin molecule, and fusions of immunologically active portions of an immunoglobulin molecule.
  • Antibody fragments include, without limitation, immunoglobulin fragments including, without limitation: single domain (Dab; e.g., single variable light or heavy chain domain), Fab, Fab', F(ab') 2 , and F(v); and fusions (e.g., via a linker) of these immunoglobulin fragments including, without limitation: scFv, scFv 2 , scFv-Fc, minibody, diabody, triabody, and tetrabody.
  • immunoglobulin fragments including, without limitation: single domain (Dab; e.g., single variable light or heavy chain domain), Fab, Fab', F(ab') 2 , and F(v); and fusions (e.g., via a linker) of these immunoglobulin fragments including, without limitation: scFv, scFv 2 , scFv-Fc, minibody, diabody, triabody, and te
  • proteins/polypeptides particularly antibodies, that bind to one or more epitopes of a protein or compound of interest, but which do not substantially recognize and bind other molecules in a sample containing a mixed population of antigenic biological molecules.
  • vector refers to a carrier nucleic acid molecule (e.g., DNA) into which a nucleic acid sequence can be inserted for introduction into a host cell where it will be replicated.
  • expression vector is a specialized vector that contains a gene or nucleic acid sequence with the necessary regulatory regions needed for expression in a host cell.
  • operably linked means that the regulatory sequences necessary for expression of a coding sequence are placed in the DNA molecule in the appropriate positions relative to the coding sequence so as to effect expression of the coding sequence.
  • This same definition is sometimes applied to the arrangement of coding sequences and transcription control elements (e.g. promoters, enhancers, and termination elements) in an expression vector.
  • This definition is also sometimes applied to the arrangement of nucleic acid sequences of a first and a second nucleic acid molecule wherein a hybrid nucleic acid molecule is generated.
  • substantially pure refers to a preparation comprising at least 50-60% by weight the compound of interest (e.g., nucleic acid, oligonucleotide, protein, etc.), particularly at least 75% by weight, or at least 90-99% or more by weight of the compound of interest. Purity may be measured by methods appropriate for the compound of interest (e.g. chromatographic methods, agarose or polyacrylamide gel electrophoresis, HPLC analysis, and the like).
  • the compound of interest e.g., nucleic acid, oligonucleotide, protein, etc.
  • Purity may be measured by methods appropriate for the compound of interest (e.g. chromatographic methods, agarose or polyacrylamide gel electrophoresis, HPLC analysis, and the like).
  • a "linker” is a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches two molecules to each other.
  • the linker comprises amino acids, particularly from 1 to about 25, 1 to about 20, 1 to about 15, or 1 to about 10 amino acids.
  • a non-human primate model with antibodies to human FVIII (inhibitors) has been generated as follows.

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Abstract

L'invention concerne des compositions et des procédés pour moduler une réponse immunitaire à l'aide de cellules T comprenant un récepteur d'antigène chimère.
PCT/US2015/045868 2014-08-19 2015-08-19 Compositions et procédés pour moduler une réponse immunitaire Ceased WO2016028879A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017218519A1 (fr) * 2016-06-13 2017-12-21 Bluebird Bio, Inc. Thérapie génique de céroïdes-lipofuscinoses neuronales
WO2018188331A1 (fr) * 2017-04-12 2018-10-18 上海优卡迪生物医药科技有限公司 Cellule car-t à stérol o-acyltransférase 1 (soat1) inhibée, son procédé d'application et son application

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130052189A1 (en) * 2010-05-06 2013-02-28 Priya S. Kishnani Method of treating patients undergoing protein replacement therapy, gene replacement therapy, or other therapeutic modalities
WO2014012001A2 (fr) * 2012-07-13 2014-01-16 The Trustees Of The University Of Pennsylvania Utilisation de cart19 pour dépléter des lymphocytes b normaux pour induire la tolérance

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130052189A1 (en) * 2010-05-06 2013-02-28 Priya S. Kishnani Method of treating patients undergoing protein replacement therapy, gene replacement therapy, or other therapeutic modalities
WO2014012001A2 (fr) * 2012-07-13 2014-01-16 The Trustees Of The University Of Pennsylvania Utilisation de cart19 pour dépléter des lymphocytes b normaux pour induire la tolérance

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017218519A1 (fr) * 2016-06-13 2017-12-21 Bluebird Bio, Inc. Thérapie génique de céroïdes-lipofuscinoses neuronales
CN109475619A (zh) * 2016-06-13 2019-03-15 蓝鸟生物公司 神经元蜡样脂褐质沉积症的基因治疗
WO2018188331A1 (fr) * 2017-04-12 2018-10-18 上海优卡迪生物医药科技有限公司 Cellule car-t à stérol o-acyltransférase 1 (soat1) inhibée, son procédé d'application et son application

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