WO2020164465A1 - 一种可助推免疫细胞在体内扩增的佐剂 - Google Patents
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- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
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- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
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- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
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- C12N2510/00—Genetically modified cells
Definitions
- the present invention belongs to the field of biomedicine technology. Specifically, the present invention provides a boosting adjuvant that can boost T cells and other immune cells to achieve artificially relatively controllable number expansion in the body, thereby enhancing the effect of immunotherapy.
- the first difficulty in immune cell therapy for solid tumors is that there are very few tumor-recognizing cells in the patient's own natural T cells, which makes it very difficult to separate tumor-recognizing T cells from autologous natural T cells.
- the long cycle and high cost of this process pose challenges to industrialization.
- many tumor-recognizing T cells are already in a state of exhaustion, and a large number of them will die after being expanded in vitro, failing to exert the expected effect. How to improve the function of immune cells used in cellular immunotherapy so as to achieve a better therapeutic effect is an unresolved problem.
- the present invention provides a boosting adjuvant for immune cell therapy.
- the boosting adjuvant can boost the expansion of the immune cells in the body, so that the number of expansions is large. Improve, thereby enhancing the effect of immunotherapy, thereby solving the above problems.
- cell can generally refer to biological cells.
- a cell can be the basic structure, function and/or biological unit of an organism.
- the cell can be derived from any organism that has one or more cells.
- Some non-limiting examples include: prokaryotic cells, eukaryotic cells, bacterial cells, archaea cells, unicellular eukaryotic cells, protozoan cells, cells from plants, algae cells, fungal cells, animal cells, including cells from invertebrates Animal cells (for example, Drosophila, cnidaria, echinoderms, nematodes, etc.), cells from vertebrates (for example, fish, amphibians, reptiles, birds, mammals) cells from mammals (for example, Pigs, cattle, goats, sheep, rodents, rats, mice, humans, etc.), etc. Sometimes cells are not derived from natural organisms (for example, cells can be synthetic, sometimes called artificial cells).
- the term "antigen" as used herein refers to a molecule or fragment thereof capable of being bound by a selective binding agent.
- the antigen may be a ligand that can be bound by a selective binding agent such as a receptor.
- the antigen may be an antigen molecule, which may be bound by a selective binding agent such as an immune protein (eg, an antibody).
- An antigen can also refer to a molecule or fragment thereof that can be used in an animal to generate antibodies capable of binding the antigen.
- mutant protein generally refers to tumor-specific antigens caused by gene mutations.
- the resulting mutant protein or fragments thereof can trigger an anti-tumor T cell response.
- genomic DNA refers to nucleic acids (eg, DNA, such as genomic DNA and cDNA) and their corresponding nucleotide sequences encoding RNA transcripts.
- genomic DNA includes inserted non-coding regions and regulatory regions, and may include 5'and 3'ends.
- the term includes transcribed sequences, including 5'and 3'untranslated regions (5'-UTR and 3'-UTR), exons and introns.
- the transcribed region will contain an "open reading frame" encoding the polypeptide.
- a “gene” contains only the coding sequence necessary to encode a polypeptide (for example, an "open reading frame” or “coding region”). In some cases, genes do not encode polypeptides, such as ribosomal RNA genes (rRNA) and transfer RNA (tRNA) genes. In some cases, the term “gene” includes not only transcribed sequences, but also non-transcribed regions, including upstream and downstream regulatory regions, enhancers and promoters. Genes can refer to "endogenous genes” or natural genes in their natural location in the genome of an organism. Genes can refer to "foreign genes” or non-natural genes.
- Non-natural genes may refer to genes that are not normally found in the host organism but are introduced into the host organism by gene transfer. Non-natural genes can also refer to genes that are not in their natural locations in the genome of an organism. A non-natural gene can also refer to a naturally occurring nucleic acid or polypeptide sequence that contains mutations, insertions, and/or deletions (e.g., non-natural sequences).
- antibody refers to protein binding molecules with immunoglobulin-like functions.
- the term antibody includes antibodies (e.g., monoclonal and polyclonal antibodies), as well as derivatives, variants and fragments thereof.
- Antibodies include, but are not limited to different classes (i.e. IgA, IgG, IgM, IgD, and IgE) and subclasses (e.g. IgG 1, IgG 2, etc.) of immunoglobulins (Ig).
- Derivatives, variants or fragments thereof may refer to functional derivatives or fragments that retain the binding specificity (e.g., complete and/or partial) of the corresponding antibody.
- Antigen-binding fragments include Fab, Fab', F(ab')2, variable fragments (Fv), single chain variable fragments (scFv), minibodies, diabodies, and single domain antibodies ("sdAb” or “nanobodies”) "Or “camelized antibody”).
- the term antibody includes antibodies and antigen-binding fragments of antibodies that have been optimized, engineered, or chemically conjugated. Examples of antibodies that have been optimized include affinity matured antibodies. Examples of antibodies that have been engineered include Fc-optimized antibodies (e.g., antibodies with optimized fragment crystallizable regions) and multispecific antibodies (e.g., bispecific antibodies).
- nucleotide generally refers to a base-sugar-phosphate combination. Nucleotides may include synthetic nucleotides. Nucleotides may include synthetic nucleotide analogs. Nucleotides can be monomeric units of nucleic acid sequences (for example, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)).
- DNA deoxyribonucleic acid
- RNA ribonucleic acid
- nucleotide may include ribonucleoside adenosine triphosphate (ATP), uridine triphosphate (UTP), cytosine triphosphate (CTP), guanosine triphosphate (GTP) and deoxyribonucleoside triphosphates such as dATP, dCTP , DITP, dUTP, dGTP, dTTP or derivatives thereof.
- ATP ribonucleoside adenosine triphosphate
- UDP uridine triphosphate
- CTP cytosine triphosphate
- GTP guanosine triphosphate
- deoxyribonucleoside triphosphates such as dATP, dCTP , DITP, dUTP, dGTP, dTTP or derivatives thereof.
- derivatives may include, for example, [ ⁇ S]dATP, 7-deaza-dGTP and 7-deaza-dATP, and nucleotide derivatives that confer nuclea
- nucleotide as used herein may refer to dideoxyribonucleoside triphosphate (ddNTP) and its derivatives.
- ddNTP dideoxyribonucleoside triphosphate
- Illustrative examples of dideoxyribonucleoside triphosphates may include, but are not limited to, ddATP, ddCTP, ddGTP, ddITP, and ddTTP.
- Nucleotides can be unlabeled or detectably labeled by well-known techniques. Marking can also be done with quantum dots. Detectable labels can include, for example, radioisotopes, fluorescent labels, chemiluminescent labels, bioluminescent labels, and enzyme labels.
- polynucleotide refers to nucleotides, deoxyribonucleotides or ribonucleotides, or their analogs, of any length in polymerized form. It is single-stranded, double-stranded, or multi-stranded.
- the polynucleotide can be exogenous or endogenous to the cell.
- the polynucleotide can exist in a cell-free environment.
- the polynucleotide may be a gene or a fragment thereof.
- the polynucleotide may be DNA.
- the polynucleotide may be RNA.
- the polynucleotide can have any three-dimensional structure and can perform any function, known or unknown.
- a polynucleotide may contain one or more analogs (e.g., a modified backbone, sugar or nucleobase).
- expression refers to one or more processes in which polynucleotides are transcribed from a DNA template (eg, into mRNA or other RNA transcripts) and/or the transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins.
- the transcript and the encoded polypeptide can be collectively referred to as "gene product”. If the polynucleotide is derived from genomic DNA, expression can include splicing mRNA in eukaryotic cells.
- up-regulation generally refers to an increase in the expression level of polynucleotides (e.g., RNA, such as mRNA) and/or polypeptide sequences relative to its expression level in the wild-type state
- downstream-regulation generally means Refers to a decrease in the expression level of polynucleotide (for example, RNA, such as mRNA) and/or polypeptide sequence relative to its expression in the wild-type state.
- modulation with respect to expression or activity refers to changing the level of expression or activity. Regulation can occur at the transcription level and/or translation level.
- peptide refers to a polymer of at least two amino acid residues connected by peptide bonds.
- the term does not imply a polymer of a specific length, nor does it imply or distinguish whether the peptide is produced using recombinant technology, chemical or enzymatic synthesis, or naturally occurring.
- the term applies to naturally occurring amino acid polymers as well as amino acid polymers containing at least one modified amino acid.
- polymers can be interrupted by non-amino acids.
- the term includes amino acid chains of any length, including full-length proteins, and proteins with or without secondary and/or tertiary structure (e.g., domains).
- amino acid polymers that have been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, oxidation, and any other operations, such as conjugation with labeling components.
- amino acid as used herein generally refers to natural and unnatural amino acids, including but not limited to modified amino acids and amino acid analogs. Modified amino acids may include natural amino acids and unnatural amino acids, which have been chemically modified to include groups or chemical moieties that do not naturally occur on amino acids. Amino acid analogs may refer to amino acid derivatives.
- amino acid includes D-amino acids and L-amino acids.
- derivatives, variants and fragments refer to a polypeptide related to a wild-type polypeptide, such as in the amino acid sequence, structure (e.g., secondary and/or tertiary) , Activity (for example, enzyme activity) and/or functionally related.
- Activity for example, enzyme activity
- derivatives, variants and fragments of polypeptides may contain one or more amino acid variations (e.g., mutations, insertions and deletions), truncations, modifications or combinations thereof.
- fusion can refer to a protein and/or nucleic acid comprising one or more non-natural sequences (e.g., portions).
- the fusion may contain one or more identical non-natural sequences.
- the fusion may contain one or more different non-natural sequences.
- the fusion may be a chimera.
- the fusion may contain a nucleic acid affinity tag.
- the fusion can include a barcode.
- the fusion may contain a peptide affinity tag. Fusions can provide subcellular localization of site-directed polypeptides (for example, nuclear localization signal (NLS) for targeting the nucleus, mitochondrial localization signal for targeting mitochondria, chloroplast localization signal for targeting chloroplast, endoplasmic reticulum ( ER) retention signal, etc.
- NLS nuclear localization signal
- ER endoplasmic reticulum
- the fusion can provide a non-natural sequence (for example, affinity tag) that can be used for tracking or purification.
- the fusion can be a small molecule, such as biotin or a dye, such as Alexa fluoro dye, Cyanine3 dye, Cyanine5 dye.
- an exogenous T cell receptor (TCR) complex refers to a TCR complex in which one or more chains of TCR are introduced into the genome of immune cells, possibly Will or may not express TCR endogenously.
- an exogenous TCR complex can refer to a TCR complex in which one or more strands of the endogenous TCR complex have one or more mutated sequences, for example at the nucleic acid or amino acid level.
- the expression of exogenous TCR on immune cells can confer epitope or antigen (for example, epitope or antigen preferentially present on the surface of cancer cells or other pathogenic cells or particles) binding specificity.
- the exogenous TCR complex may include TCR- ⁇ , TCR- ⁇ chain, CD3- ⁇ chain, CD3- ⁇ chain, CD3- ⁇ chain, or any combination thereof introduced into the genome.
- the strand introduced into the genome can replace the endogenous strand.
- subject refers to vertebrates, preferably mammals, such as humans.
- Mammals include, but are not limited to, mice, apes, humans, farm animals, sports animals, and pets. It also includes tissues, cells and their progeny of biological entities obtained in vivo or cultured in vitro.
- treatment refers to methods used to obtain beneficial or desired results, including but not limited to therapeutic benefits and/or preventive benefits.
- treatment may include administration of booster adjuvants and immune cells disclosed herein.
- Therapeutic benefit refers to any treatment-related improvement or effect of one or more diseases, disorders or symptoms in treatment.
- the composition can be administered to subjects who are at risk of developing a particular disease, disorder, or symptom, or to subjects who report one or more physiological symptoms of the disease, even if the disease, disorder, or symptom It may not show up yet.
- an effective amount refers to the amount of the composition, for example, a combination comprising the booster adjuvant of the present disclosure and/or immune cells such as lymphocytes (eg, T lymphocytes and/or NK cells) It is sufficient to produce the desired activity when administered to a subject in need.
- the term “therapeutically effective” means that the amount of the composition is sufficient to delay manifestation, prevent progression, reduce or alleviate at least one symptom of the condition treated by the method of the present invention.
- the term “genetic profile” refers to information about specific genes, including variation and gene expression in an individual or a certain type of tissue. Genetic profiles can be used for neoantigen selection.
- the term “somatic mutation profile” refers to information about specific genes related to somatic mutations, including but not limited to specific genes produced by somatic mutations. Somatic mutation profiles can be used for neoantigen selection.
- booster adjuvant refers to an agent capable of assisting immune cell therapy, which is characterized by having a booster antigen (Booster Antigen, BA), and the booster antigen is a specific
- Booster Antigen BA
- the antigen can be specifically recognized by a certain specific therapeutic immune cell in the body, and the adjuvant can be activated with the help of the booster antigen and help the immune cell to expand quantitatively in the body.
- the specific therapeutic immune cell recognizes the booster antigen by expressing an artificially modified chimeric antigen receptor (CAR) on the therapeutic immune cell, and the CAR specifically recognizes the booster antigen.
- CAR is a chimeric antigen receptor (chimeric antigen receptor targeting a Booster Antigen, hereinafter or simply "anti-Booster Antigen-CAR” or “aBA-CAR”) that can target and boost antigens, and its structure includes a recognizable aid The antigen binding domain of the antibody that pushes the antigen, such as the variable region.
- the booster antigen can be a mutant type of a membrane protein widely expressed by any human cell, or a mutant type of a membrane protein expressed by tumor cells.
- These membrane proteins include a type I RTK (for example, including EGFR).
- ROR receptor family ROR1 and ROR2 ROR receptor family ROR1 and ROR2
- XIII type RTK e.g. discoid domain receptor (DDR) family such as DDR1 and DDR2
- XIV type RTK e.g. RET receptor family such as RET
- XV type RTK for example, KLG receptor family, including PTK7
- XVI type RTK for example, RYK receptor family including Ryk
- XVII type RTK for example, MuSK receptor family such as MuSK
- CD47, CD70, NKG2D Or any derivative, variant or fragment thereof.
- the booster antigen may comprise at least one extracellular region of a catalytic receptor (eg, receptor tyrosine kinase (RTK)) or any derivative, variant or fragment thereof (eg, ligand binding domain ), or mutants of these fragments.
- a catalytic receptor eg, receptor tyrosine kinase (RTK)
- RTK receptor tyrosine kinase
- the booster antigen comprises a class I RTK (e.g., the epidermal growth factor (EGF) receptor family including EGFR; the ErbB family including ErbB-2, ErbB-3, and ErbB-4), a class II RTK (
- the insulin receptor family includes INSR, IGF-1R and IRR), class III RTK (for example, the platelet-derived growth factor (PDGF) receptor family, including PDGFR- ⁇ , PDGFR- ⁇ , CSF-1R, KIT/SCFR and FLK2/FLT3), type IV RTK (for example, fibroblast growth factor (FGF) receptor family, including FGFR-1, FGFR-2, FGFR-3 and FGFR-4), type V RTK (for example, vascular endothelial growth Factor (VEGF) receptor family, including VEGFR1, VEGFR2 and VEGFR3), class VI RTK (for example, hepatocyte growth factor (HGF) receptor family, including hepatocyte growth factor receptor (HGFR/MET
- GEF epi
- the booster antigen may comprise a mutant type of RTK or any derivative, variant or fragment thereof.
- RTK ligands include growth factors, cytokines and hormones.
- Growth factors include, for example, members of the epidermal growth factor family (eg, epidermal growth factor or EGF, heparin-binding EGF-like growth factor or HB-EGF, transforming growth factor- ⁇ or TGF- ⁇ , amphiregulin or AR, epidermal growth factor Regulin or EPR, epigen, betacellulin or BTC, neuregulin-1 or NRG1, neuregulin-2 or NRG2, neuregulin-3 or NRG3, neuregulin-4 or NRG4), fibroblast growth factor family (Such as FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15/19, FGF16, FGF17, FGF18, FGF20, F
- Hormones include, for example, members of the insulin/IGF/relaxin family (e.g., insulin, insulin-like growth factors, relaxin family peptides, including relaxin 1, relaxin 2, relaxin 3, Leydig cell-specific insulin-like Peptide (gene INSL3), early placental insulin-like peptide (ELIP) (gene INSL4), insulin-like peptide 5 (gene INSL5) and insulin-like peptide 6.
- members of the insulin/IGF/relaxin family e.g., insulin, insulin-like growth factors, relaxin family peptides, including relaxin 1, relaxin 2, relaxin 3, Leydig cell-specific insulin-like Peptide (gene INSL3), early placental insulin-like peptide (ELIP) (gene INSL4), insulin-like peptide 5 (gene INSL5) and insulin-like peptide 6.
- members of the insulin/IGF/relaxin family e.g., insulin, insulin-like growth factors, relaxin
- the booster antigen includes at least the extracellular region of the catalytic receptor (eg, ligand binding domain), such as receptor threonine/serine kinase (RTSK), or any derivative, variant, or Fragments, or fragments containing antibody variable regions with these fragments as antigens.
- the booster antigen may comprise type I RTSK, type II RTSK or any derivative, variant or fragment thereof.
- the booster antigen may comprise a type I receptor, or any derivative, variant or fragment thereof, selected from: ALK1 (ACVRL1), ALK2 (ACVR1A), ALK3 (BMPR1A), ALK4 (ACVR1B), ALK5 (TGF ⁇ R1), ALK6 (BMPR1B) and ALK7 (ACVR1C).
- the booster antigen may comprise a type II receptor, or any derivative, variant or fragment selected from the group consisting of TGF ⁇ R2, BMPR2, ACVR2A, ACVR2B and AMHR2 (AMHR).
- the booster antigen comprises TGF- ⁇ .
- the booster antigen includes RTSK or any derivative or mutant thereof.
- the booster antigen is a B cell surface protein or fragment thereof.
- the B cell surface protein can be any protein that can be found on the surface of B cells.
- Non-limiting examples include CD1d, CD5, CD10, CD11a, CD19, CD20, CD21, CD22, CD23, CD24, CD25, CD27, CD28, CD29, CD34, CD37, CD38, CD40, CD44, CD45, CD49b, CD69, CD72 .
- the antigen interaction domain of the CAR can bind to surface proteins on non-B cells, as long as the binding to the surface proteins does not significantly damage the general health of the host or the immune system.
- the surface protein is a surface protein on immune cells. In some embodiments, the surface protein is a surface protein on cells other than immune cells.
- the surface protein may be selected from CD31, CD32 (A, B), CD33, CD34, CD35, CD36, CD37, CD38, CD39, CD40, CD41, CD42 (a, b, c, d) , CD43, CD44, CD45, CD46, CD47, CD48, CD49 (a, b, c, d, e, f), CD50, CD51, CD52, CD53, CD54, CD55, CD56, CD57, CD58, CD59, CD61, CD62 (E, L, P), CD63, CD64 (A, B, C), CD66 (a, b, c, d, e, f), CD68, CD69, CD70, CD71, CD72, CD73, CD74, CD78 , CD79 (a, b), CD80, CD81, CD82, CD83, CD84, CD85 (a, d, e, h, j, k), CD86, CD87, CD88, CD
- the booster antigen is all or partial fragments of NK cells, granulocytes, red blood cells, and platelet surface proteins.
- the booster antigens are surface markers or transmembrane proteins or fragments of pathogens such as viruses, bacteria, and fungi, including HPV virus, Epstein-Barr virus, Helicobacter pylori (HP), hepatitis B virus (HBV) , HIV (HIV).
- pathogens such as viruses, bacteria, and fungi, including HPV virus, Epstein-Barr virus, Helicobacter pylori (HP), hepatitis B virus (HBV) , HIV (HIV).
- the booster antigen is any human intracellular protein or fragment thereof.
- the booster antigen is any human extracellular secreted protein or fragment thereof.
- the booster antigen is a wild-type or mutant type of all or part of a human natural protein, or a wild-type or mutant type of all or part of a plurality of human natural proteins.
- the booster antigen is CD19 or EGFRviii (including complete EGFRviii, or EGFRviiit, that is, truncated EGFRviii), or includes CD19 and/or CD86 and/or CD137L and/or mbIL15 (membrane-bound interleukin 15, membrane-bound (IL15) and/or IL15Ra ( ⁇ subunit of IL15 receptor), or a composition comprising EGFRviii and/or CD86 and/or CD137L and/or mbIL15 and/or IL15Ra.
- the booster adjuvant may be a protein, a compound, a complex, or a cell (hereinafter referred to as a "booster cell”), or an artificial nanomaterial containing a booster antigen.
- the booster antigen can be coupled (e.g., via covalent and/or non-covalent bonds) to the surface of the particle (e.g., nanoparticle).
- the particles may be any particulate material including organic and/or inorganic materials.
- the particles can have various shapes and sizes.
- the particles may be about 1 nanometer (nm) to about 50 microns ( ⁇ m) in at least one dimension.
- the particles may be at least about 1 nm, 5 nm, 10 nm, 50 nm, 100 nm, 500 nm, 1 ⁇ m, 5 ⁇ m, 10 ⁇ m, 50 ⁇ m or more in at least one dimension.
- the particles may be up to about 50 ⁇ m, 10 ⁇ m, 5 ⁇ m, 1 ⁇ m, 500 nm, 100 nm, 50 nm, 10 nm, 5 nm, 1 nm or less in at least one dimension.
- the particles can be nanoparticles, microparticles, nanospheres, microspheres, nanorods, microrods, nanofibers, nanobelts and the like.
- Examples of particles include metal nanoparticles (eg, gold nanoparticles, silver nanoparticles, and iron nanoparticles), intermetallic semiconductor nanoparticles, core-shell nanoparticles, particles with an inorganic core having a polymer shell, and having a polymer shell The organic core particles, and their mixtures.
- the particles may be organic nanoparticles, such as cross-linked polymers, hydrogel polymers, biodegradable polymers, polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL) , Copolymer, polysaccharide, starch, cellulose, chitosan, polyhydroxyalkanoate (PHA), PHB, PHV, lipid, peptide, peptide amphiphile, polypeptide (such as protein) or a combination thereof.
- Particles that present B cell surface proteins on the surface can be introduced into immune cells containing CARs that bind the B cell surface proteins in vitro.
- particles that present B cell surface proteins can be introduced in vivo (e.g., local or systemic injection) together with immune cells containing CAR. These particles can be used to expand the CAR-containing immune cell population in vitro or in vivo.
- the booster adjuvant is a booster cell
- the booster cell is derived from the patient's autologous or foreign peripheral blood mononuclear cells (PBMC) or any of B cells, T cells, NK cells, etc.
- PBMC peripheral blood mononuclear cells
- the cell is a natural unmodified cell, or a modified cell, or a B cell or NK cell (such as NK92) or K562 cell that has been immortalized.
- the booster adjuvant is a booster cell (such as a T cell), and the booster antigen is expressed on the booster cell across the membrane, and the booster antigen is composed of an extracellular binding domain and a transmembrane.
- a fusion protein composed of a region, wherein the extracellular binding domain is a structure recognizable by a specific therapeutic immune cell (such as EGFRviii or CD19), and the transmembrane region is a part or part of a protein naturally expressed by the booster cell Full structure (such as CD3).
- the "antigen binding domain" of aBA-CAR can include any protein or molecule that can bind to the booster antigen.
- antigen binding domains include but are not limited to monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, murine antibodies or functional derivatives, variants or fragments thereof, including but not limited to Fab , Fab', F(ab')2, Fv, single-chain Fv (scFv), minibodies, diabodies and single-domain antibodies such as heavy chain variable domains (VH), the light of camelid-derived Nanobodies Chain variable domain (VL) and variable domain (VHH).
- VH heavy chain variable domains
- VL camelid-derived Nanobodies Chain variable domain
- VHH variable domain
- the antigen binding domain comprises at least one of Fab, Fab', F(ab')2, Fv and scFv.
- the antigen binding domain comprises an antibody mimic.
- Antibody mimics are molecules that can bind to target molecules with an affinity equivalent to that of antibodies, including single-chain binding molecules, cytochrome b562-based binding molecules, fibronectin or fibronectin-like protein scaffolds (for example, adnectin), lipids Carrier protein scaffold, calixarene scaffold, A domain and other scaffolds.
- the antigen binding domain comprises a transmembrane receptor or any derivative, variant or fragment thereof.
- the antigen binding domain may comprise at least the ligand binding domain of a transmembrane receptor.
- the "antigen binding domain" of aBA-CAR may comprise scFV.
- the scFv can be derived from antibodies with known variable region sequences.
- scFv can be derived from antibody sequences obtained from available mouse hybridomas.
- the scFv can be obtained from the entire exon sequencing of tumor cells or primary cells.
- scFv can be modified.
- scFv can be modified in various ways.
- scFv can be mutated so that the scFv can have a higher affinity for its target.
- the affinity of the scFv to its target can be optimized for targets that are expressed at low levels on normal tissues.
- This optimization can be performed to minimize potential toxicity, such as hypercytokineemia.
- the cloned scFv with higher affinity for the target membrane-bound form may be better than its soluble form counterpart. If certain targets can also be detected in different levels of soluble forms, and their targeting can cause unintended toxicity, such as hypercytokineemia, this modification can be made.
- the antigen binding domain of the aBA-CAR of this system can be connected to the intracellular signal transduction domain through the transmembrane domain.
- the transmembrane domain may be a transmembrane segment.
- the transmembrane domain of the subject's CAR can anchor the CAR to the plasma membrane of cells, such as immune cells.
- the transmembrane segment comprises a polypeptide.
- the transmembrane polypeptide connecting the antigen binding domain of the CAR and the intracellular signal transduction domain can have any suitable polypeptide sequence.
- the transmembrane polypeptide comprises the polypeptide sequence of the transmembrane portion of the endogenous or wild-type transmembrane protein.
- the transmembrane polypeptide comprises a polypeptide sequence having at least one (eg, at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions, deletions, and polypeptides. The insertion is compared to the transmembrane portion of the endogenous or wild-type transmembrane protein.
- the transmembrane polypeptide comprises a non-natural polypeptide sequence, such as the sequence of a polypeptide linker.
- the polypeptide linker can be flexible or rigid.
- the polypeptide linker can be structured or unstructured.
- the transmembrane polypeptide transmits the signal from the extracellular region of the cell to the intracellular region through the antigen binding domain.
- the natural transmembrane portion of CD28 can be used in aBA-CAR. In other cases, the natural transmembrane portion of CD8 ⁇ can also be used in aBA-CAR.
- the CAR of the present disclosure may include a signaling domain involved in immune cell signaling or any derivative, variant or fragment thereof.
- the intracellular signal transduction domain of CAR can induce the activity of immune cells containing CAR.
- Intracellular signal transduction domains can transduce effector function signals and direct cells to perform specialized functions.
- the signal transduction domain may include the signal transduction domain of other molecules. In some cases, truncated portions of the signaling domain are used for CAR.
- the intracellular signaling domain comprises multiple signaling domains involved in immune cell signaling, or any derivative, variant or fragment thereof.
- the intracellular signaling domain may comprise at least 2 immune cell signaling domains, for example, at least 2, 3, 4, 5, 7, 8, 9 or 10 immune cell signaling domains.
- Immune cell signaling domains can participate in regulating the primary activation of the TCR complex in a stimulating or inhibitory manner.
- the intracellular signaling domain may be the signaling domain of the T cell receptor (TCR) complex.
- the intracellular signal transduction domain of the CAR of the present invention may include Fc ⁇ receptor (Fc ⁇ R), Fc ⁇ receptor (Fc ⁇ R), Fc ⁇ receptor (Fc ⁇ R), neonatal Fc receptor (FcRn), CD3, CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , CD4, CD5, CD8, CD21, CD22, CD28, CD32, CD40L (CD154), CD45, CD66d, CD79a, CD79b, CD80, CD86, CD278 (also known as ICOS), CD247 ⁇ , CD247 ⁇ , DAP10, DAP12, Signaling domains of FYN, LAT, Lck, MAPK, MHC complex, NFAT, NF- ⁇ B, PLC- ⁇ , iC3b, C3dg, C3d and Zap70.
- Fc ⁇ receptor Fc ⁇ receptor
- Fc ⁇ R Fc ⁇ receptor
- Fc ⁇ R Fc ⁇ receptor
- Fc ⁇ R neonatal Fc receptor
- the signaling domain includes an immunoreceptor tyrosine-based activation motif or ITAM.
- ITAM-containing signal transduction domain can include two repeated amino acid sequences YxxL/I, which are separated by 6-8 amino acids, where each x is independently any amino acid, resulting in the conserved motif YxxL/Ix (6-8) YxxL /I.
- the ITAM-containing signaling domain can be modified, for example, by phosphorylation. Phosphorylated ITAM can serve as a docking site for other proteins, such as proteins involved in various signal transduction pathways.
- the primary signaling domain comprises a modified ITAM domain, such as a mutated, truncated and/or optimized ITAM domain, which has altered (e.g., increased Or reduced) activity.
- the intracellular signaling domain of the CAR comprises an FcyR signaling domain (e.g., ITAM).
- the FcyR signaling domain can be selected from FcyRI (CD64), FcyRIIA (CD32), FcyRIIB (CD32), FcyRIIIA (CD16a) and FcyRIIIB (CD16b).
- the intracellular signaling domain comprises an Fc ⁇ R signaling domain (eg, ITAM).
- the Fc ⁇ R signaling domain can be selected from Fc ⁇ RI and Fc ⁇ RII (CD23).
- the intracellular signaling domain comprises an FcaR signaling domain (eg, ITAM).
- the FcaR signaling domain can be selected from FcaRI (CD89) and Fca/ ⁇ R.
- the intracellular signaling domain comprises a CD3 ⁇ signaling domain.
- the primary signaling domain comprises the ITAM of CD3 ⁇ .
- the intracellular signaling domain of the CAR comprises an immunoreceptor tyrosine-based inhibitory motif or ITIM.
- the signal transduction domain containing ITIM may contain a conserved amino acid sequence (S/I/V/LxYxxI/V/L), which is present in the cytoplasmic tail of some inhibitory receptors of the immune system.
- the main signaling domain comprising ITIM can be modified by enzymes (e.g., Src kinase family members (e.g. Lck)), such as phosphorylation. After phosphorylation, other proteins, including enzymes, can be recruited to ITIM.
- proteins include, but are not limited to, enzymes such as phosphotyrosine phosphatase SHP-1 and SHP-2, inositol phosphatase called SHIP, and proteins with one or more SH2 domains (such as ZAP70).
- enzymes such as phosphotyrosine phosphatase SHP-1 and SHP-2, inositol phosphatase called SHIP
- proteins with one or more SH2 domains such as ZAP70.
- Intracellular signaling domains may include BTLA, CD5, CD31, CD66a, CD72, CMRF35H, DCIR, EPO-R, Fc ⁇ RIIB (CD32), Fc receptor-like protein 2 (FCRL2), Fc receptor-like protein 3 (FCRL3) , Fc receptor-like protein 4 (FCRL4), Fc receptor-like protein 5 (FCRL5), Fc receptor-like protein 6 (FCRL6), protein G6b (G6B), interleukin 4 receptor (IL4R), immunoglobulin Superfamily receptor translocation related 1 (IRTA1), immunoglobulin superfamily receptor translocation related 2 (IRTA2), killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1), killer cell immunoglobulin-like receptor 2DL2 ( KIR2DL2), killer cell immunoglobulin-like receptor 2DL3 (KIR2DL3), killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4), killer cell immunoglobulin-like receptor 2DL5 (KIR2
- the intracellular signaling domain of the CAR comprises at least 2 ITAM domains (e.g., at least 3, 4, 5, 6, 7, 8, 9 Or 10 ITAM domains).
- the intracellular signaling domain comprises at least 2 ITIM domains (eg, at least 3, 4, 5, 6, 7, 8, 9 or 10 ITIM domains) (For example, at least 2 main signaling domains).
- intracellular signaling domains include ITAM and ITIM domains.
- the intracellular signaling domain of the CAR may include a costimulatory domain.
- the costimulatory domain for example from a costimulatory molecule, can provide a costimulatory signal for immune cell signal transduction, such as signal transduction from ITAM and/or ITIM domain, for example, for activation and/or loss Live immune cell activity.
- the costimulatory domain can be used to modulate proliferation and/or survival signals in immune cells.
- the costimulatory signaling domain comprises MHC class I protein, MHC class II protein, TNF receptor protein, immunoglobulin-like protein, cytokine receptor, integrin, signaling lymphocyte activation molecule (SLAM protein), activates the signaling domain of NK cell receptor, BTLA or Toll ligand receptor.
- the costimulatory domain comprises a signaling domain of a molecule selected from the group consisting of: 2B4/CD244/SLAMF4, 4-1BB/TNFSF9/CD137, B7-1/CD80, B7-2/CD86, B7 -H1/PD-L1, B7-H2, B7-H3, B7-H4, B7-H6, B7-H7, BAFF R/TNFRSF13C, BAFF/BLyS/TNFSF13B, BLAME/SLAMF8, BTLA/CD272, CD100(SEMA4D) , CD103, CD11a, CD11b, CD11c, CD11d, CD150, CD160 (BY55), CD18, CD19, CD2, CD200, CD229/SLAMF3, CD27 ligand/TNFSF7, CD27/TNFRSF7, CD28, CD29, CD2F-10/SLAMF9, CD30 ligand/TNFSF8, CD30/TNFRSF8, CD300a
- the intracellular signaling domain comprises multiple costimulatory domains, such as at least two, such as at least 3, 4, or 5 costimulatory domains.
- the costimulatory signal transduction area can provide a signal that is coordinated with the primary effector activation signal, and can fulfill the requirement of activating T cells.
- the addition of a costimulatory domain to the CAR can enhance the efficacy and durability of the immune cells provided herein.
- the proliferation of immune cells may refer to the expansion of immune cells.
- the proliferation of immune cells can refer to the phenotypic changes of immune cells.
- the proliferation of immune cells containing the CAR herein, particularly aBA-CAR may be greater than the proliferation of immune cells lacking the CAR.
- the proliferation of immune cells containing CAR may be about 5 times to about 10 times, about 10 times to about 20 times, about 20 times to about 30 times, about 30 times to about 40 times, about 40 times that of cells lacking CAR.
- the proliferation of immune cells containing CAR may be about 5 times to about 10 times, about 10 times to about 20 times, about 20 times to about 30 times, about 30 times to about 40 times, about 40 times to about 40 times that of CAR lacking cells.
- Proliferation is determined at least about 12, 24, 36, 48, 60, 72, 84, or 96 hours after contacting the booster antigen with the immune cells.
- the enhancement of proliferation can be determined in vitro or in vivo.
- proliferation can include quantifying the number of immune cells. Quantitative immune cells may include flow cytometry, trypan blue exclusion, and/or blood count. Proliferation can also be determined by phenotypic analysis of immune cells.
- the CAR structure may include an expression control element, which may be a switching element that regulates the expression of CAR or CAR-T cells and/or causes suicide or apoptosis of CAR-T or CAR-NK cells, such as TET-ON.
- an expression control element which may be a switching element that regulates the expression of CAR or CAR-T cells and/or causes suicide or apoptosis of CAR-T or CAR-NK cells, such as TET-ON.
- the therapeutic immune cells are T cells, or NK cells.
- the therapeutic immune cells are artificially modified T cells, or NK cells, such as CAR-T, CAR-NK, TCR-T, TCR-NK cells.
- the therapeutic immune cells of the present disclosure are tumor infiltrating lymphocytes (TIL), which specifically bind to tumor-associated antigens, including but not limited to neoantigens.
- TIL tumor infiltrating lymphocytes
- the modified TIL may contain chimeric stimulatory molecules.
- the chimeric stimulatory molecule may comprise a polypeptide extracellular domain (PED) that binds to a neoantigen.
- PED can be fused with the intracellular domain (ICD) of a costimulatory molecule that mediates immune cell activation signals.
- ICD intracellular domain
- the combination of chimeric stimulatory molecules and neoantigens can generate immune cell activation signals in the modified TIL.
- PED may be the extracellular domain of the surface protein of unmodified TIL.
- examples of PED include antibodies, and derivatives, variants, and fragments thereof.
- the present disclosure provides modified T cells that have dual recognition characteristics.
- One aspect of the dual recognition refers to the recognition of target cells, that is, the T cells can recognize and Kill target cells, which are cells that are harmful to the human body, such as tumor cells, or non-tumor cells such as viruses and bacteria; on the other hand, it refers to the recognition of boosting antigens, that is, the immune cells can independently recognize boosting Antigens or adjuvants with boosting antigens are activated to increase their number.
- the present disclosure provides T cells modified with aBA-CAR.
- the T cells have dual recognition properties.
- One aspect of the dual recognition refers to the recognition of target cells, that is, the T cells are It can recognize and kill target cells, which are cells that are harmful to the human body, such as tumor cells, or non-tumor cells such as viruses and germs; on the other hand, it refers to the recognition of booster antigens, that is, the immune cells can use aBA-CAR independently recognizes booster antigens or adjuvants with booster antigens and is activated to expand its number.
- the present disclosure provides T cells modified with aBA-CAR and TCR or CAR (another CAR different from aBA-CAR), the T cell having dual recognition characteristics, one of the dual recognition properties
- the aspect refers to the recognition of target cells, that is, the T cells have artificial (or exogenous) TCR or CAR (another CAR other than aBA-CAR), which can be identified and combined with the help of the artificial TCR or CAR.
- Kill target cells which are cells that are harmful to the human body, such as tumor cells, or non-tumor cells such as viruses and germs; on the other hand, it refers to the recognition of booster antigens, that is, the immune cells can use aBA-CAR Independently recognize the booster antigen or the adjuvant with booster antigen to be activated and expand its number.
- the target of the immune cell for recognizing the target cell and the target for recognizing the booster antigen are different or the same.
- the present disclosure provides aBA-CAR modified tumor-recognizing T cells or tumor antigen-reactive T cells, the T cells have dual recognition characteristics, one aspect of the dual recognition refers to tumor cells Recognition, that is, on the one hand, the T cell can recognize and kill tumor cells; on the other hand, it refers to the recognition of the booster antigen, that is, the immune cell can independently recognize the booster antigen or with booster by means of aBA-CAR
- the adjuvant of the antigen is activated to increase its number.
- Tumor-recognizing T cells can recognize neoantigens (neoantigen), or tumor-associated antigens (TAA), or cancer test antigens, or viruses with the help of natural unmodified TCRs.
- Antigens such as viral antigens on the surface of cells infected with HPV or EBV virus and become cancerous, etc.
- tumor-recognizing T cells can be induced by vaccines, or they can be obtained from tumor infiltrating lymphocytes (TIL), or they can use certain markers of peripheral blood (such as PD1, TIM3, CD137, CD39, CD28, etc.) Of positive or negative screening.
- Tumor-recognizing T cells can also recognize tumors by using artificially modified CARs or TCRs to form CAR-Ts or TCR-Ts to recognize related tumor cells.
- Tumor infiltrating lymphocytes can be any cells obtained from tumors.
- TIL can be a cell that has migrated to a tumor.
- TIL can be cells that have infiltrated the tumor.
- TILs are white blood cells that have migrated from the bloodstream of the subject into the tumor.
- the TIL may be, for example, T cells, B cells, monocytes or natural killer (NK) cells.
- the modified TIL comprises CD8+ cytotoxic T cells (lymphocytes), Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells or M1 macrophages.
- the immune cell population containing TIL may be a mixed cell population.
- the TIL population may include cells of different phenotypes, cells of different degrees of differentiation, cells of different lineages, or any combination thereof.
- TIL can usually be defined functionally by biochemistry, the use of cell surface markers, or its ability to penetrate tumors and affect treatment.
- TIL can be classified based on the expression of one or more of the following biomarkers: CD4, CD8, TCR ⁇ , CD25, CD27, CD28, CD39, CD56, CD137, CCR7, CD45Ra, CD95, PD-1 and TIM-3 .
- the modified TIL expresses at least one of PD-1, CD39, CD137, and TIM-3.
- TIL can be functionally defined by its ability to penetrate solid tumors when reintroduced into the patient.
- the modified TIL includes a "primary TIL”, which refers to a TIL obtained from a patient tissue sample.
- the modified TIL includes a "secondary TIL", which refers to a TIL that has been amplified or proliferated.
- TIL can exhibit specific binding to neoantigens.
- the TCR complex of TIL confers antigen binding specificity (eg, neoantigen binding).
- the immune cells are tumor infiltrating lymphocytes (TIL).
- TIL may be, for example, T cells, B cells, monocytes or natural killer (NK) cells.
- TIL contains CD8+ cytotoxic T cells (lymphocytes), Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, or M1 macrophages.
- TIL can express at least one of PD-1, CD137 and TIM-3.
- the modified TIL includes "primary TIL", which refers to TIL obtained from a patient tissue sample.
- the modified TIL includes a "secondary TIL", which refers to a TIL that has been amplified or proliferated.
- TIL can leave the tumor tissue and exist in the peripheral blood. In some embodiments, TIL may not be derived from tumor tissue. In some embodiments, TIL can be obtained by isolating peripheral blood mononuclear cells (PBMC) by apheresis, or further by screening and enriching by one or more markers such as PD1, TIM3, CD137, and CD39.
- PBMC peripheral blood mononuclear cells
- the present disclosure provides modified T cells that specifically bind to neoantigens, the modified T cells not only including aBA-CAR, but also enhanced receptors.
- the enhancement receptor may comprise the extracellular domain (ECD) of the protein. ECD can be fused with the intracellular domain (ICD) of a costimulatory molecule that mediates immune cell activation signals. Enhancing the binding of receptor and ligand can generate immune cell activation signals in modified T cells, but not immune cell inactivation signals.
- the modified T cell may comprise a T cell receptor (TCR) complex, which exhibits specific binding to the neoantigen.
- TCR complex is an endogenous TCR complex.
- the TCR is an exogenous TCR complex.
- the TCR complex of the modified immune cell eg, endogenous or exogenous
- can confer antigen binding specificity eg, neoantigen binding
- the present disclosure provides a modified T cell comprising an endogenous TCR complex that specifically binds a neoantigen, the modified T cell comprising a chimeric stimulatory molecule, wherein the chimeric stimulatory molecule Contains:
- the bound polypeptide extracellular domain (PED) includes but is not limited to the membrane protein on the cell of tumor cells, wherein the PED is fused with the intracellular domain (ICD) of a costimulatory molecule that mediates immune cell activation signals, Wherein the chimeric stimulating molecule is combined with the chimeric stimulating molecule.
- the membrane protein generates the immune cell activation signal in the modified T cell.
- a modified immune cell such as a modified T cell or a modified TIL provided herein
- Enhanced receptors of modified cells can be used to provide further control of immune cell activity, such as but not limited to immune cell activation and expansion. Enhancing the binding of the receptor to the ligand in the modified immune cell (eg, modified T cell or modified TIL) can trigger an immune cell activation signal in the modified immune cell instead of an immune cell inactivation signal. Triggering the immune cell activation signal in the modified immune cell instead of the immune cell inactivation signal can minimize the immunosuppressive effect in the immune cell. Minimizing immune suppression in immune cells can increase the effectiveness of immune cells in immune responses, for example, by increasing immune cell cytotoxicity against target cells (eg, tumor cells).
- target cells eg, tumor cells
- the enhanced receptor may contain the extracellular domain (ECD) of the protein, which triggers an immune cell signal after binding to its ligand in an unmodified immune cell.
- the signal can be an inactivation signal, an activation signal, or Neither activation nor deactivation signal.
- the protein can be a signal transduction receptor or any functional fragment, derivative or variant thereof.
- the signaling receptor can be a membrane-bound receptor. In response to ligand binding, signaling receptors can induce one or more signaling pathways in the cell. In some cases, the signaling receptor may be a non-membrane-bound receptor.
- the enhanced receptor may comprise a fragment of a receptor selected from G protein coupled receptors (GPCRs), such as extracellular domains; integrin receptors; cadherin receptors; catalytic receptors (such as kinases); death receptors ; Checkpoint receptors; cytokine receptors; chemokine receptors; growth factor receptors; hormone receptors; and immune receptors.
- GPCRs G protein coupled receptors
- the booster receptor comprises a fragment of the immune checkpoint receptor, which can participate in the regulation of the immune system.
- Non-limiting examples of such receptors include, but are not limited to, programmed cell death 1 (PD-1, or PD1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), B and T lymphocyte attenuating agents (BTLA ), killer immunoglobulin-like receptor (KIR), indoleamine 2,3-dioxygenase (IDO), lymphocyte activation gene-3 (LAG3), T cell immunoglobulin mucin 3 (TIM- 3) T cell immune receptor (TIGIT) with Ig and ITIM domains, SIRP ⁇ , NKG2D.
- PD-1, or PD1 programmed cell death 1
- CTLA-4 cytotoxic T lymphocyte-associated protein 4
- BTLA-4 B and T lymphocyte attenuating agents
- KIR killer immunoglobulin-like receptor
- IDO indoleamine 2,3-dioxygenase
- LAG3 lymph
- the enhanced receptor comprises at least an extracellular fragment of TCR, which can participate in recognizing neoantigens of target cells (eg, cancer cell antigens or tumor antigens).
- the enhanced receptor may comprise the extracellular variable region of the TCR alpha and/or beta chain.
- the enhanced receptor may comprise an immune checkpoint receptor or any derivative, variant or fragment thereof.
- the enhanced receptor can bind to an antigen comprising any suitable immune checkpoint receptor ligand or any derivative, variant or fragment thereof.
- suitable immune checkpoint receptor ligands include, but are not limited to, B7-1, B7-H3, B7-H4, HVEM (herpes virus entry medium), AP2M1, CD80, CD86, SHP-2, PPP2R5A, MHC (e.g., I Class, Class II), CD47, CD70, PD-L1 (or PDL1) and PD-L2.
- the region that enhances the binding of receptors to such ligands may be the natural receptors of such ligands or monoclonal antibodies of such ligands.
- the enhanced receptor comprises a fragment of a cytokine receptor.
- Cytokine receptors can perform a variety of functions, non-limiting examples of which include immune cell regulation and mediation of inflammation.
- the enhanced receptor comprises a cytokine receptor, such as a type I cytokine receptor or a type II cytokine receptor, or any derivative, variant or fragment thereof.
- the enhanced receptor comprises an interleukin receptor (e.g., IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-9R, IL-11R, IL-12R, IL-13R, IL-15R, IL-21R, IL-23R, IL-27R and IL-31R), a colony stimulating factor receptor (for example, erythropoietin receptor, CSF-1R, CSF-2R, GM-CSFR and G-CSFR), hormone receptors/neuropeptide receptors (for example, growth hormone receptor, prolactin receptor and leptin receptor), or any derivative, variant or fragment thereof .
- an interleukin receptor e.g., IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-9R, IL-11R, IL-12R, IL-13R, IL-15R, IL-21R, IL
- the enhanced receptor comprises a type II cytokine receptor, or any derivative, variant or fragment thereof.
- enhanced receptors include interferon receptors (eg, IFNAR1, IFNAR2, and IFNGR), interleukin receptors (eg, IL-10R, IL-20R, IL-22R, and IL-28R), tissue Factor receptors. (Also known as platelet tissue factor), or any derivative, variant or fragment thereof.
- the extracellular binding domain of the enhanced receptor can be any antibody or fragment of an antibody.
- the antigen to which the antibody binds can be a membrane protein widely expressed by human cells or a membrane protein expressed by tumor cells.
- membrane proteins include type I RTKs (e.g., epidermal growth factor (EGF) receptor family including EGFR; ErbB family including ErbB-2, ErbB-3 and ErbB-4), type II RTKs (e.g., insulin receptor Body family includes INSR, IGF-1R and IRR), type III RTK (for example, platelet-derived growth factor (PDGF) receptor family, including PDGFR- ⁇ , PDGFR- ⁇ , CSF-1R, KIT/SCFR and FLK2/FLT3) , Type IV RTK (for example, fibroblast growth factor (FGF) receptor family, including FGFR-1, FGFR-2, FGFR-3 and FGFR-4), Type V RTK (for example, vascular endothelial growth factor (VEGF) Receptor family, including V
- the membrane protein that enhances receptor binding may comprise at least one extracellular region of a catalytic receptor (e.g., receptor tyrosine kinase (RTK)) or any derivative, variant or fragment thereof (e.g., Ligand binding domains), or fragments comprising antibody variable regions with these fragments as antigens.
- a catalytic receptor e.g., receptor tyrosine kinase (RTK)
- RTK receptor tyrosine kinase
- Ligand binding domains e.g., Ligand binding domains
- the membrane protein that enhances receptor binding includes class I RTK (eg, epidermal growth factor (EGF) receptor family including EGFR; ErbB including ErbB-2, ErbB-3, and ErbB-4 Family), class II RTK (for example, insulin receptor family includes INSR, IGF-1R and IRR), class III RTK (for example, platelet-derived growth factor (PDGF) receptor family, including PDGFR- ⁇ , PDGFR- ⁇ , CSF) -1R, KIT/SCFR and FLK2/FLT3), class IV RTK (for example, fibroblast growth factor (FGF) receptor family, including FGFR-1, FGFR-2, FGFR-3 and FGFR-4), class V RTK (for example, the vascular endothelial growth factor (VEGF) receptor family, including VEGFR1, VEGFR2, and VEGFR3), class VI RTK (for example, the hepatocyte growth factor (HGF) receptor family, including the hepatocyte growth factor receptor (HGFR/MET)
- GEF epi
- ROR receptor family ROR1 and ROR2 type XIII RTK (e.g., discoid Domain receptor (DDR) family (such as DDR1 and DDR2), XIV type RTK (such as RET receptor family such as RET), XV type RTK (such as KLG receptor family, including PTK7), XVI type RTK (such as RYK receptor
- DDR discoid Domain receptor
- XIV type RTK such as RET receptor family such as RET
- XV type RTK such as KLG receptor family, including PTK7
- XVI type RTK such as RYK receptor
- the family includes Ryk), XVII type RTK (for example, MuSK receptor family such as MuSK), CD47, CD70, NKG2D, or any derivative, variant or fragment thereof.
- the membrane protein to which the enhanced receptor can bind comprises RTK or any derivative thereof, and the enhanced receptor of a variant or fragment can bind to a protein comprising any suitable RTK ligand or any derivative, variant or fragment thereof.
- RTK ligands include growth factors, cytokines and hormones.
- Growth factors include, for example, members of the epidermal growth factor family (eg, epidermal growth factor or EGF, heparin-binding EGF-like growth factor or HB-EGF, transforming growth factor- ⁇ or TGF- ⁇ , amphiregulin or AR, epidermal growth factor Regulin or EPR, epigen, betacellulin or BTC, neuregulin-1 or NRG1, neuregulin-2 or NRG2, neuregulin-3 or NRG3, neuregulin-4 or NRG4), fibroblast growth factor family (Such as FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF13, FGF14, FGF15/19, FGF16, FGF17, FGF18, FGF20, FGF21 and FGF23), vascular endothelial growth Factor families (such as VEGF-A, VEGF-B, VEGF-C, VEGF-D
- Hormones include, for example, members of the insulin/IGF/relaxin family (e.g., insulin, insulin-like growth factors, relaxin family peptides, including relaxin 1, relaxin 2, relaxin 3, Leydig cell-specific insulin-like Peptide (gene INSL3), early placental insulin-like peptide (ELIP) (gene INSL4), insulin-like peptide 5 (gene INSL5) and insulin-like peptide 6).
- members of the insulin/IGF/relaxin family e.g., insulin, insulin-like growth factors, relaxin family peptides, including relaxin 1, relaxin 2, relaxin 3, Leydig cell-specific insulin-like Peptide (gene INSL3), early placental insulin-like peptide (ELIP) (gene INSL4), insulin-like peptide 5 (gene INSL5) and insulin-like peptide 6).
- members of the insulin/IGF/relaxin family e.g., insulin, insulin-like growth factors
- the membrane protein that enhances receptor binding includes at least the extracellular region of the catalytic receptor (eg, ligand binding domain), such as receptor threonine/serine kinase (RTSK), or any derivative thereof Compounds, variants or fragments, or fragments comprising antibody variable regions with these fragments as antigens.
- the membrane protein capable of enhancing receptor binding may comprise type I RTSK, type II RTSK or any derivative, variant or fragment thereof.
- the enhanced receptor may comprise a type I receptor, or any derivative, variant or fragment thereof, selected from: ALK1 (ACVRL1), ALK2 (ACVR1A), ALK3 (BMPR1A), ALK4 (ACVR1B), ALK5 (TGF ⁇ R1), ALK6 (BMPR1B) and ALK7 (ACVR1C).
- the enhanced receptor may comprise a type II receptor, or any derivative, variant or fragment selected from the group consisting of TGF ⁇ R2, BMPR2, ACVR2A, ACVR2B and AMHR2 (AMHR).
- the enhanced receptor comprises TGF- ⁇ receptor or any derivative, variant or fragment thereof.
- the enhanced receptor-binding membrane protein comprising RTSK or any derivative, variant or fragment thereof may bind to an antigen comprising any suitable RTSK ligand or any derivative, variant or fragment thereof, or comprise these fragments A fragment of the variable region of an antibody as an antigen.
- the booster receptor may comprise an intracellular domain (ICD) of a costimulatory molecule that triggers an immune cell activation signal.
- Co-stimulatory molecules can bind ligands.
- costimulatory molecules can be activated by ligand-responsive proteins.
- costimulatory molecules can be used to modulate proliferation and/or survival signals in immune cells.
- the ICD is the intracellular domain of a costimulatory molecule selected from MHC class I protein, MHC class II protein, TNF receptor protein, immunoglobulin-like protein, cytokine receptor, Integrin, signaling lymphocyte activation molecule (SLAM protein), activated NK cell receptor, BTLA or Toll ligand receptor.
- the costimulatory molecule or costimulatory domain comprises a signaling domain of a molecule selected from the group consisting of: 2B4/CD244/SLAMF4, 4-1BB/TNFSF9/CD137, B7-1/CD80, B7-2 /CD86, B7-H1/PD-L1, B7-H2, B7-H3, B7-H4, B7-H6, B7-H7, BAFF R/TNFRSF13C, BAFF/BLyS/TNFSF13B, BLAME/SLAMF8, BTLA/CD272, CD100 (SEMA4D), CD103, CD11a, CD11b, CD11c, CD11d, CD150, CD160 (BY55), CD18, CD19, CD2, CD200, CD229/SLAMF3, CD27 ligand/TNFSF7, CD27/TNFRSF7, CD28, CD29, CD2F- 10/SLAMF9, CD3, CD30 ligand/TNFSF8, CD30
- the ECD and ICD of the enhanced receptor can be connected by a transmembrane domain, for example by a transmembrane segment.
- the transmembrane segment comprises a polypeptide.
- the transmembrane polypeptide can have any suitable polypeptide sequence.
- the transmembrane polypeptide comprises the polypeptide sequence of the transmembrane portion of the endogenous or wild-type transmembrane protein.
- the transmembrane polypeptide comprises a polypeptide sequence having at least one (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) amino acid substitutions, deletions, and polypeptides.
- the transmembrane polypeptide comprises a non-natural polypeptide sequence, such as the sequence of a polypeptide linker.
- the polypeptide linker can be flexible or rigid.
- the polypeptide linker can be structured or unstructured.
- the transmembrane polypeptide transmits a signal from the ECD to the ICD, such as a signal indicative of ligand binding.
- the ECD comprises a transmembrane domain.
- the ICD comprises a transmembrane domain.
- ICD can mediate the production of immune cell activation signals (or immune cell activation signals) in immune cells.
- immune cell activation signals are mediated by activating factors.
- the activator can be an immunomodulatory molecule.
- Activating factors can bind, activate or stimulate T cells or other immune cells to regulate their activity.
- activating factors can be secreted from immune cells.
- the activating factor can be, for example, a soluble cytokine, a soluble chemokine or a growth factor molecule.
- Non-limiting examples of activating factors that can mediate the activation of immune cells include soluble cytokines such as IL-1, IL-2, IL-6, IL-7, IL-8, IL-10, IL-12, IL. -15, IL-21, tumor necrosis factor (TNF), transforming growth factor (TGF), interferon (IFN) or any functional fragment or variant thereof.
- soluble cytokines such as IL-1, IL-2, IL-6, IL-7, IL-8, IL-10, IL-12, IL. -15, IL-21, tumor necrosis factor (TNF), transforming growth factor (TGF), interferon (IFN) or any functional fragment or variant thereof.
- TNF tumor necrosis factor
- TGF transforming growth factor
- IFN interferon
- Immune cell activation signals may include or result in clonal expansion of modified immune cells (eg, modified TIL or modified T cells); released by modified immune cells (eg, modified TIL or modified T cells) Cytokines; cytotoxicity of modified immune cells (for example, modified TIL or modified T cells); proliferation of modified immune cells (for example, modified TIL or modified T cells); modified immune cells (for example, modified TIL or modified T cells) differentiation, dedifferentiation or transdifferentiation; movement and/or transport of modified immune cells (for example, modified TIL or modified T cells); modified immune cells (for example, modified TIL Or modified T cells) depletion and/or reactivation; through the release of other intercellular molecules, metabolites, chemical compounds, or combinations thereof through modified immune cells (for example, modified TIL or modified T cells).
- modified immune cells eg, modified TIL or modified T cells
- Cytokines cytotoxicity of modified immune cells (for example, modified TIL or modified T cells); proliferation of modified immune cells (for example, modified TIL or modified
- the immune cell activation signal includes or results in clonal expansion of immune cells.
- Clonal expansion can include the production of daughter cells produced by immune cells.
- Daughter cells resulting from clonal expansion may contain enhanced receptors.
- the clonal expansion of modified immune cells may be greater than that of comparable immune cells lacking enhanced receptors.
- the clonal expansion of modified immune cells can be about 5 to about 10 times, about 10 to about 20 times, about 20 to about 30 times, about 30 times to about comparable immune cells lacking enhanced receptors.
- determining clonal expansion can include quantifying the number of immune cells, for example, in the presence and absence of the enhanced receptor and after the ligand binds to the enhanced receptor.
- the quantification of many immune cells can be achieved by a variety of techniques, non-limiting examples of which include flow cytometry, trypan blue exclusion, and blood count.
- the immune cell activation signal comprises or causes the immune cell to release cytokines.
- immune cell activity includes or results in the release of intercellular molecules, metabolites, chemical compounds, or combinations thereof.
- the cytokines released by the modified immune cells may include the release of IL-1, IL-2, IL-4, IL-5, IL-6, IL-13, IL-17, IL-21, IL-22, IFN ⁇ , TNF ⁇ , CSF, TGF ⁇ , Granzyme, etc.
- cytokine release can be quantified using enzyme-linked immunosorbent assay (ELISA), flow cytometry, western blotting, and the like.
- ELISA enzyme-linked immunosorbent assay
- modified immune cells may be greater than that of comparable immune cells lacking enhanced receptors.
- the modified immune cells provided herein can produce approximately 1 times, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times compared to comparable immune cells lacking enhanced receptors, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 times, 200 times , 250 times, or more than 300 times cytokine release.
- the modified immune cell can be compared to comparable immune cells lacking the enhanced receptor (e.g., unmodified) Shows increased secretion of cytokines.
- the secreted cytokine is IFN ⁇ or IL-2.
- cytokine release can be quantified in vitro or in vivo.
- the immune cell activation signal comprises or causes the immune cell to produce cytotoxicity.
- the cytotoxicity of the modified immune cells provided herein can be used to kill target cells. Immune cells or populations of immune cells expressing enhanced receptors can induce the death of target cells. Killing target cells can be used in a variety of applications, including but not limited to treating diseases or conditions in which cell populations need to be eliminated or where it is desired to inhibit their proliferation. Cytotoxicity can also refer to the release of cytotoxic cytokines by immune cells, such as IFN ⁇ or granzyme.
- the modified immune cells provided herein can alter (i) the release of cytotoxins, such as perforin, granzyme and granulysin, and/or (ii) pass through Fas-between T cells and target cells. Fas ligand interaction induces apoptosis.
- cytotoxicity can be quantified by cytotoxicity assays, including co-culture assays, ELISPOT, chromium release cytotoxicity assays, and the like.
- the cytotoxicity of the modified immune cells provided herein may be greater than the cytotoxicity of comparable immune cells lacking enhanced receptors.
- the modified immune cells can exhibit Increased cytotoxicity against target cells.
- the modified immune cells of the present invention can be about 5%, 10%, 15%, 20%, 25%, 30%, 35% more cytotoxic to target cells. 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175% or 200% .
- the modified immune cell of the present invention can induce the death of target cells, and the induced target cell death is at least 5%, 10%, 15%, 20%, 25%, 30%, 35 more than comparable immune cells without the modification. %, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175% or 200%.
- the immune cells provided herein can induce apoptosis in target cells that display target epitopes (e.g., neoantigens) on their surfaces.
- cytotoxicity can be determined in vitro or in vivo.
- determining cytotoxicity may include determining the level of disease after administration of the modified immune cells provided herein compared to the level of disease before administration. In some embodiments, determining cytotoxicity may include determining the level of disease after administration of the modified immune cells provided herein and the level of disease after administration of comparable immune cells lacking enhanced receptors.
- the immune cell activation signal comprises or results in the proliferation of immune cells.
- the proliferation of immune cells may refer to the expansion of immune cells.
- the proliferation of immune cells can refer to the phenotypic changes of immune cells.
- the proliferation of the modified immune cells of the present disclosure may be greater than the proliferation of comparable immune cells lacking enhanced receptors.
- the proliferation of the modified immune cells provided herein may be about 5 to about 10 times, about 10 to about 20 times, about 20 to about 30 times, about 30 to about 30 times that of Kobe immune cells lacking enhanced receptors.
- proliferation can be determined by quantifying the number of immune cells. Quantifying many immune cells can include flow cytometry, trypan blue exclusion, and/or blood count. Proliferation can also be determined by phenotypic analysis of immune cells.
- the immune cell activation signal may include or cause the differentiation, dedifferentiation, or transdifferentiation of immune cells.
- the differentiation, dedifferentiation or transdifferentiation of immune cells can be determined by flow cytometry to evaluate the phenotypic expression of markers of differentiation, dedifferentiation or transdifferentiation on the cell surface.
- the modified immune cells provided herein have an increased ability to differentiate compared to comparable immune cells lacking enhanced receptors.
- the modified immune cells provided herein have increased dedifferentiation capacity compared to comparable immune cells lacking enhanced receptors.
- the modified immune cells provided herein have increased dedifferentiation capacity compared to comparable immune cells lacking enhanced receptors.
- the modified immune cells provided herein have greater transdifferentiation capabilities than comparable immune cells lacking enhanced receptors.
- the immune cell activation signal may include or cause the movement and/or transportation of immune cells.
- movement can be determined by quantifying the localization of immune cells to target sites.
- the modified immune cells provided herein can be quantified at the target site after administration, such as at a site that is not the target site. Quantification can be performed by isolating the lesion and quantifying the many immune cells containing enhanced receptors (e.g., tumor infiltrating lymphocytes). The movement and/or transportation of immune cells containing enhanced receptors may be greater than the movement and/or transportation of comparable immune cells lacking enhanced receptors.
- enhanced receptors e.g., tumor infiltrating lymphocytes
- the number of immune cells containing enhanced receptors at the target site may be about 5 times, 10 times, 15 times, 20 times, 25 times that of comparable immune cells lacking enhanced receptors. Times, 30 times, 35 times or 40 times.
- the transwell migration assay can also be used to determine trafficking in vitro.
- the number of immune cells containing enhanced receptors at the target site for example, in a transwell migration assay, may be about 5 times, 10 times, or 15 times the number of comparable immune cells lacking enhanced receptors , 20 times, 25 times, 30 times, 35 times or 40 times.
- the immune cell activation signal may include or cause the depletion and/or activation of immune cells.
- the depletion and/or activation of immune cells can be determined by phenotypic analysis by flow cytometry or microscopic analysis. For example, quantitatively and/or qualitatively determine the expression level of depletion markers such as programmed cell death protein 1 (PD1), lymphocyte activation gene 3 protein (LAG3), 2B4, CD160, Tim3 and T cell immune receptor (TIGIT) with immunoglobulin and ITIM domains.
- PD1 programmed cell death protein 1
- LAG3 lymphocyte activation gene 3 protein
- 2B4 CD160
- T cell immune receptor T cell immune receptor
- immune cells lose their effector functions and become exhausted in a layered manner. Due to fatigue, functions such as IL-2 production and cytokine expression and high proliferation capacity may be lost.
- Exhaustion may also be a defect in the production of IFN ⁇ , TNF and chemokines and degranulation.
- the depletion or activation of the modified immune cells provided herein can be greater than the depletion or activation of comparable immune cells lacking enhanced receptors.
- the immune cells provided herein may experience an increase of at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold compared to comparable immune cells lacking enhanced receptors. , 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 150 Times, 200 times, 250 times or more than 300 times depletion or activation.
- the immune cells contained herein can experience at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold reduction compared to comparable immune cells lacking enhanced receptors, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times , 150 times, 200 times, 250 times or more than 300 times depletion or activation.
- the binding of the target cell to the enhanced receptor can generate an immune cell activation signal in the immune cell modified with the enhanced receptor.
- immune cells modified with the enhanced receptor behave Improved new antigen binding.
- immune cells modified with enhanced receptors such as TIL, neoantigen-reactive T cells, CAR-T, TCR-T, NK, etc.
- immune cells without enhanced modification (respectively corresponding to Compared with the aforementioned TIL, neoantigen-reactive T cells, CAR-T, TCR-T, NK, etc.)
- the ECD that enhances the receptor is PD1 or PDL1 monoclonal antibody, and ICD is any certain costimulatory molecule.
- the tumor suppressor signal that can be effectively overcome to a certain extent is not limited to PDL1, but can also include CD47, TIM -3 ligands such as Galectin-9, TIGIT ligands such as CD155 and CD122 or PVR, CTLA-4 ligands such as B7 inhibit immune cells.
- the ECD of the enhanced receptor is SIRP ⁇ or CD47 monoclonal antibody
- ICD is any costimulatory molecule
- the tumor suppressor signal that can be effectively overcome to a certain extent is not only from CD47, but also from PDL1 , TIM-3 ligands such as Galectin-9, TIGIT ligands such as CD155 and CD122 or PVR, CTLA-4 ligands such as B77 inhibit immune cells.
- the receptor-enhancing ECD is a TIM-3 ligand monoclonal antibody such as Galectin-9 monoclonal antibody or TIM-3 monoclonal antibody
- ICD is any certain costimulatory molecule, which can be effectively overcome to a certain extent.
- Tumor suppression signals are not limited to TIM-3 ligands such as Galectin-9, but can also include PDL1, TIGIT ligands such as CD155 and CD122 or PVR, CTLA-4 ligands such as B77 on immune cells.
- the receptor-enhancing ECD is a monoclonal antibody of TIGIT or its ligands, such as CD155 monoclonal antibody or CD122 monoclonal antibody or PVR monoclonal antibody.
- ICD is any certain costimulatory molecule, which can be effectively overcome to a certain extent.
- the tumor suppressor signal of TIGIT not only comes from TIGIT ligands such as CD155 and CD122 or PVR, but can also include suppressive signals from PDL1, TIM-3 ligands such as Galectin-9, and CTLA-4 ligands such as B77 on immune cells.
- the ECD of the enhanced receptor is VISTA
- ICD is any costimulatory molecule
- the tumor suppressor signal that can be effectively overcome to a certain extent is not limited to the VISTA ligand
- the ECD of the enhanced receptor is CTLA -4
- the tumor suppressor signals that can be effectively overcome to a certain extent are not only from CTLA-4 ligands such as B7, but also from PDL1, CD47, TIM-3 ligands such as Galectin-9, TIGIT ligands such as CD155 and CD122 or PVR, CTLA-4 ligands such as B77 inhibit immune cells.
- T cells modified with aBA-CAR and enhanced receptors also carry artificial (or exogenous) T cell receptors (TCR) or another chimeric antigen receptor CAR, when TCR or When CAR can recognize target cells, T cells modified with enhanced receptors have stronger immune cell activation function than T cells without enhanced receptor modification; when artificial TCR or another CAR cannot recognize target cells, T cells modified with enhanced receptors do not have a stronger immune cell activation function than T cells without enhanced receptor modification.
- TCR T cell receptors
- the T cell receptor (TCR) complex that exhibits specific binding to the neoantigen may be an endogenous TCR complex or an exogenous TCR complex.
- the TCR complex of the modified immune cell eg, endogenous or exogenous
- can confer antigen binding specificity eg, neoantigen binding
- the present disclosure provides a modified immune cell that specifically binds to a neoantigen
- the modified immune cell comprises: (a) a chimeric stimulatory molecule comprising a polypeptide extracellular structure that binds to the neoantigen Domain (PED), where PED is fused with the intracellular domain (ICD) of a costimulatory molecule that mediates immune cell activation signals, and where the combination of chimeric stimulatory molecules and neoantigens generates immune cell activation signals in modified immune cells , And (b) aBA-CAR, which contains (i) a domain capable of binding and boosting antigen interaction; (ii) a transmembrane domain; (iii) an intracellular signaling domain.
- PED may be the extracellular domain of the surface protein of unmodified TIL.
- examples of PED include antibodies, and derivatives, variants, and fragments thereof.
- the present disclosure provides modified immune cells that specifically bind to neoantigens or tumor-associated antigens (TAA) or cancer test antigens or antigens derived from viruses (such as HPV, EBV), wherein the modified Immune cells include: (a) a natural TCR that can specifically bind to neoantigens or a genetically engineered exogenous TCR; (b) an enhanced receptor containing the extracellular domain (ECD) of the protein, where the ECD is fused to mediate The intracellular domain (ICD) of the costimulatory molecule of immune cell activation signal, and in which the enhanced receptor and ligand produce immune cell activation signal instead of immune cell inactivation signal in the modified immune cell, and (c) aBA- CAR, which contains (i) a domain capable of binding and boosting antigen interaction; (ii) a transmembrane domain; (iii) an intracellular signal transduction domain; among the above three a, b, and c, c
- the present disclosure provides modified tumor infiltrating lymphocytes (TIL) that specifically bind to neoantigens, wherein the modified immune cells comprise: (a) natural TCR that can specifically bind to neoantigens; b) An enhanced receptor containing the extracellular domain (ECD) of the protein.
- TIL tumor infiltrating lymphocytes
- ECD extracellular domain
- ECD is fused with the intracellular domain (ICD) of a costimulatory molecule that mediates immune cell activation signals, and where the molecule is converted into a ligand to generate immune cell activation signals instead of immune cell inactivation signals in the modified TIL, and ( c) aBA-CAR, which contains (i) a domain capable of binding and promoting antigen interaction; (ii) a transmembrane domain; (iii) an intracellular signal transduction domain.
- a, b, and c c is indispensable.
- a, b, and c coexist, The cells in which the three coexist are called Super TIL (STIL).
- the present disclosure provides modified immune cells that overexpress cytokines, such as chemokines, where the immune cells are (i) tumor infiltrating lymphocytes (TIL); (ii) interstitial tumor infiltrating lymphocytes ( sTIL); or (iii) T cells that exhibit specific binding to the antigen.
- cytokines such as chemokines
- the immune cells are (i) tumor infiltrating lymphocytes (TIL); (ii) interstitial tumor infiltrating lymphocytes (sTIL); or (iii) T cells that exhibit specific binding to the antigen.
- TIL tumor infiltrating lymphocytes
- sTIL interstitial tumor infiltrating lymphocytes
- T cells that exhibit specific binding to the antigen.
- the modified immune cell overexpressing the chemokine can be any of the modified immune cells provided herein.
- Cytokines refer to proteins released by cells (for example, chemokines, interferons, lymphokines, interleukins, and tumor necrosis factor), which can affect cell behavior. Cytokines are produced by a variety of cells, including immune cells such as macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts and various stromal cells. A given cytokine can be produced by more than one type of cell. Cytokines can participate in systemic or local immune regulation.
- Certain cytokines can act as pro-inflammatory cytokines.
- Pro-inflammatory cytokines refer to cytokines involved in inducing or amplifying an inflammatory response.
- Pro-inflammatory cytokines can produce an immune response together with various cells of the immune system, such as neutrophils and leukocytes.
- Certain cytokines can act as anti-inflammatory cytokines.
- Anti-inflammatory cytokines refer to cytokines that participate in reducing inflammation. In some cases, anti-inflammatory cytokines can modulate the pro-inflammatory cytokine response.
- Some cytokines can act as pro-inflammatory cytokines and anti-inflammatory cytokines.
- Certain cytokines, such as chemokines can play a role in chemotaxis. Chemokines can induce targeted chemotaxis in nearby responding cells.
- the expression of cytokines with pro-inflammatory and/or chemotactic functions can be up-regulated in immune cells. Up-regulating the expression of cytokines with pro-inflammatory and/or chemotactic functions can be used, for example, to stimulate an immune response against target cells in immunotherapy.
- cytokines examples include, but are not limited to, lymphokines, monocytes, and traditional polypeptide hormones.
- Cytokines include growth hormones, such as human growth hormone, N-methionyl human growth hormone and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; pro relaxin; glycoprotein hormones, such as Follicle Stimulating Hormone (FSH), Thyroid Stimulating Hormone (TSH) and Luteinizing Hormone (LH); Liver Growth Factor; Fibroblast Growth Factor; Prolactin; Placental Prolactin; Tumor Necrosis Factor- ⁇ ; Mullerian Inhibitors; Mice Gonadotropin-related peptide; Inhibin; Activin; Vascular endothelial growth factor; Integrin; Thrombopoietin (TPO); Nerve growth factor such as NGF- ⁇ ; Platelet growth factor; Transforming growth factor (IL- ⁇ ; Platelet growth factor; Trans
- Cytokine receptor refers to a receptor protein that binds to cytokine. Cytokine receptors can be membrane-bound and soluble.
- the overexpressed cytokine is a member of the interleukin (IL-1) family (such as a ligand), a member of the IL-1 receptor family, a member of the interleukin-6 (IL-6) family (such as Ligand), IL-6 receptor, interleukin-10 (IL-10) family member (such as ligand), IL-10 receptor, interleukin-12 (IL-12) family member (such as ligand) ), IL-12 receptor, interleukin-17 (IL-17) family member (such as ligand) or IL-17 receptor.
- IL-1 interleukin
- IL-6 interleukin-6
- IL-10 interleukin-10
- IL-12 interleukin-12
- IL-17 interleukin-17
- the overexpressed cytokine is a member of the interleukin-1 (IL-1) family or a related protein; a member of the tumor necrosis factor (TNF) family or a related protein; a member of the interferon (IFN) family or a related protein ; Interleukin-6 (IL-6) family members or related proteins; or chemokines or related proteins.
- IL-1 interleukin-1
- TNF tumor necrosis factor
- IFN interferon
- IL-6 Interleukin-6 family members or related proteins
- chemokines or related proteins chemokines or related proteins.
- the cytokine is selected from IL18, IL18BP, IL1A, IL1B, IL1F10, IL1F3/IL1RA, IL1F5, IL1F6, IL1F7, IL1F8, IL1RL2, IL1F9, IL33, BAFF/BLyS/TNFSF138, 4-1BBL, CD153/ CD30L.
- /TNFSF8 CD40LG, CD70, Fas ligand/FASLG/CD95L/CD178, EDA-A1, TNFSF14/LIGHT/CD258, TNFA, LTA/TNFB/TNFSF1, LTB/TNFC, CD70/CD27L/TNFSF7, TNFSF10/TRAIL/APO -2L (CD253), RANKL/OPGL/TNFSF11 (CD254), TNFSF12, TNF- ⁇ /TNFA, TNFSF13, TL1A/TNFSF15, OX-40L/TNFSF4/CD252, CD40L/CD154/TNFSF5, IFNA1, IFNA10, IFNA13, IFNA14 , IFNA2, IFNA4, IFNA7, IFNB1, IFNE, IFNG, IFNZ, IFNA8, IFNA5/IFNaG, IFN ⁇ /IFNW1, CLCF1, CNTF, IL11, IL31, IL6,
- Cytokine expression can be determined by measuring one or more of the cell culture medium in which the modified immune cells are grown (e.g., in vitro production) or serum obtained from subjects with modified immune cells (e.g., in vivo production). The presence of various cytokines is assessed. Cytokine levels can be quantified in various suitable units using any suitable assay, including concentration. In some embodiments, cytokine proteins are detected. In some embodiments, the mRNA transcript of the cytokine is detected.
- cytokine assays include enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunofluorescence assay, radioimmunoassay, antibody arrays allowing parallel detection of various cytokines in samples, bead-based arrays, quantitative PCR, microarrays Wait.
- ELISA enzyme-linked immunosorbent assay
- immunoblotting immunofluorescence assay
- radioimmunoassay antibody arrays allowing parallel detection of various cytokines in samples, bead-based arrays, quantitative PCR, microarrays Wait.
- Other suitable methods may include proteomics methods (2-D gel, MS analysis, etc.).
- the cytokine overexpressed by the modified immune cells provided herein is a chemokine.
- the chemokine may be, for example, CC chemokine, CXC chemokine, C chemokine and CX3C chemokine.
- the chemokine overexpressed by the modified immune cells is a CC chemokine selected from CCL1, CCL2, CCL3, CCL4, CCL5, CCL6, CCL7, CCL8, CCL9, CCL10, CCL11, CCL12, CCL13, CCL14, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL23, CCL24, CCL25, CCL26, CCL27 and CCL28.
- the chemokine is a CXC chemokine selected from CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16 and CXCL17.
- the chemokine overexpressed by the modified immune cells is a C chemokine selected from XCL1 and XCL2.
- the chemokine overexpressed by immune cells is a CX3C chemokine, and the CX3C chemokine is CX3CL1.
- an immune cell that is a genetically modified NK cell other than the aBA-CAR modification.
- this article provides a NK cell, which is a CAR-NK cell modified by CAR gene other than aBA-CAR modification, and this CAR gene modification other than aBA-CAR confers NK
- the characteristics of cells specifically recognizing and killing target cells; the CAR genetic modification other than aBA-CAR may include a partial structure of NKG2D.
- the booster adjuvant is a cascade booster system composed of n kinds of booster cells of the present invention, wherein the n is a positive integer, and the first-stage booster cells express the first booster.
- Push antigen (BA1) second-level booster cells express the second booster antigen (BA2) and aBA1-CAR that specifically targets the first booster antigen
- third-level booster cells express the third Booster antigen (BA3) and aBA2-CAR that specifically targets the second booster antigen, ...
- the nth booster cells express the nth booster antigen (BAn) and target the n-1th booster
- BAn nth booster antigen
- the aBA n-1 -CAR that pushes the antigen, the n- th booster antigen BAn can be recognized by the therapeutic immune cells, and the booster antigens of different levels are different from each other.
- the number n of the multi-stage boost system of cascade amplification can be any positive integer in the range of 1-10000000.
- the booster cells starting from the second stage can be amplified in vivo by BA-CAR activated by the upper booster antigen, and different levels of booster
- the pusher cells can be the same type of cells (for example, all T cells, or all NK cells), different types of cells, or a mixture of multiple types of cells.
- the present invention provides an immune cell therapy adjuvant pharmaceutical composition, which is characterized in that the pharmaceutical composition comprises the boosting adjuvant described herein.
- the present invention provides a drug combination for immune cell therapy, characterized in that the drug combination includes the booster adjuvant described herein, and the therapeutic immune cell of the present invention, wherein the therapeutic immune cell is combined with the therapeutic immune cell.
- the pharmaceutical composition is infused in a single or consecutive multiple times at an appropriate point in time, so that the therapeutic immune cells can be activated by the adjuvant in the pharmaceutical composition and amplified in number, thereby identifying and Kill target cells.
- the present invention provides a method for treating cancer, which is characterized in that the immune cell therapy adjuvant pharmaceutical composition or the immune cell therapy drug combination described herein is applied, specifically, the therapeutic immune cell is combined with the Immune cell therapy adjuvant drugs are infused in a single or multiple consecutive times at the right time.
- the present disclosure provides a method of treating cancer in a subject, which comprises: (a) administering a modified TIL to the subject, and the modified PBMC in peripheral blood undergoes PD1, TIM3, CD137, CD39- One or more positively screened T cells, modified T cells or modified immune cells, any of any of the embodiments.
- the aspect here (b) Under the condition of inducing modified TIL, modified T cell, modified T cell or modified immune cell against the cytotoxicity of target cell, make the target cell of cancer expressing neoantigen and The modified TIL, the modified selected T cell, the modified T cell or the modified immune cell are contacted to induce the death of the cancer target cell.
- the present disclosure provides a method of expanding a T cell population, the method comprising: (a) providing a T cell population comprising at least the modified immune cells of any one of the various embodiments of the aspect. Here; (b) exposing the T cell population to a booster antigen to achieve expansion of the T cell population.
- the present disclosure provides a method for amplifying a T cell population, which comprises: (a) introducing a nucleic acid encoding aBA-CAR into the T cell population, thereby generating aBA-CAR-expressing cells or cell population, wherein aBA -CAR contains (i) a domain that interacts with an antigen specifically recognized by the CAR; (ii) a transmembrane domain; (iii) an intracellular signal transduction domain; (b) the cell population that expresses aBA-CAR can assist Push antigen contact, thereby generating an expanded and/or activated immune cell population. Wherein, the antigen is not specifically expressed by tumor target cells.
- the present disclosure provides a composition comprising one or more polynucleotides encoding one or more of the following: (a) an enhanced receptor, wherein the enhanced receptor comprises an extracellular domain of a protein (ECD), where the ECD is fused with the intracellular domain (ICD) of a costimulatory protein that mediates immune cell activation signals; (b) an antigen-specific T cell receptor complex, or one or more components thereof.
- ECD extracellular domain of a protein
- ICD intracellular domain
- an antigen-specific T cell receptor complex or one or more components thereof.
- the present disclosure provides a composition comprising one or more polynucleotides encoding one or more of the following: (a) an antigen-specific T cell receptor complex, or one or more combinations thereof Points; (b) aBA-CAR, which contains (i) a domain capable of binding and boosting antigen interaction; (ii) a transmembrane domain; (iii) an intracellular signaling domain.
- the present disclosure provides a composition comprising one or more polynucleotides encoding one or more of the following: (a) an enhanced receptor, wherein the enhanced receptor comprises an extracellular domain of a protein (ECD), wherein the ECD is fused with an intracellular domain (ICD) of a costimulatory protein that mediates immune cell activation signals; (b) aBA-CAR, which includes (i) an interaction domain capable of binding and boosting antigen ; (Ii) Transmembrane domain; (iii) Intracellular signaling domain.
- ECD extracellular domain of a protein
- ICD intracellular domain
- a costimulatory protein that mediates immune cell activation signals
- aBA-CAR which includes (i) an interaction domain capable of binding and boosting antigen ; (Ii) Transmembrane domain; (iii) Intracellular signaling domain.
- the present disclosure provides a composition comprising one or more polynucleotides encoding one or more of the following: (a) an enhanced receptor, wherein the enhanced receptor comprises an extracellular domain of a protein (ECD), wherein the ECD is fused with an intracellular domain (ICD) of a costimulatory protein that mediates immune cell activation signals; (b) an antigen-specific T cell receptor complex, or one or more groups thereof Points; (c) aBA-CAR, which contains (i) a domain capable of binding and promoting an antigen interaction; (ii) a transmembrane domain; (iii) an intracellular signaling domain.
- ECD extracellular domain of a protein
- ICD intracellular domain
- a costimulatory protein that mediates immune cell activation signals
- an antigen-specific T cell receptor complex or one or more groups thereof Points
- aBA-CAR which contains (i) a domain capable of binding and promoting an antigen interaction; (ii) a transmembr
- promoters that can be used with the composition of the present disclosure include promoters that are active in eukaryotic, mammalian, non-human mammalian, or human cells.
- the promoter can be an inducible or constitutively active promoter.
- the promoter may be tissue or cell specific.
- Non-limiting examples of suitable eukaryotic promoters may include promoters from the following sources: early cytomegalovirus (CMV), herpes simplex virus (HSV) thymidine kinase , Early and late SV40, long terminal repeat (LTR) from retrovirus, human elongation factor-1 promoter (EF1), a cytomegalovirus (CMV) fused with chicken beta active promoter (CAG) Hybrid constructs of enhancers, murine stem cell virus promoter (MSCV), phosphoglycerate kinase-1 locus promoter (PGK) and mouse metallothionein-I.
- the promoter may be a fungal promoter.
- the promoter may be a plant promoter.
- a database of plant promoters can be found (for example, PlantProm).
- the expression vector may also contain a ribosome binding site for translation initiation and a transcription terminator.
- the expression vector may also include suitable sequences for amplifying expression.
- the modified immune cells can specifically bind to neoantigens and/or neoepitopes.
- Neoantigens and neoepitopes usually refer to tumor-specific mutations, which in some cases trigger anti-tumor T cell responses.
- the entire exome sequencing method can be used to identify these endogenous mutations (Tran E et al., "Cancer immunotherapy based on mutation-specific CD4+ T cells in patients with epithelial cancer", Science 344:641- 644 (2014)).
- Modified immune cells containing enhanced receptors e.g., modified TIL or modified T cells
- the neoantigens bound by immune cells can be expressed on target cells and, for example, are encoded by mutations in endogenous genes. In some cases, the neoantigens or epitopes specifically bound by immune cells may be encoded by mutated genes.
- the gene can be selected from: ABL1, ACO1 1997, ACVR2A, AFP, AKT1, ALK, ALPPL2, ANAPC1, APC, ARID1A, AR, AR-v7, ASCL2, ⁇ 2M, BRAF, BTK, C15ORF40, CDH1, CLDN6, CNOT1, CT45A5 , CTAG1B (code NY-ESO-1), DCT, DKK4, EEF1B2, EEF1DP3, EGFR, EIF2B3, env, EPHB2, ERBB3, ESR1, ESRP1, FAM111B, FGFR3, FRG1B, GAGE1, GAGE 10, GATA3, GBP3, HER2, IDH1, JAK1, KIT, KRAS, LMAN1, MABEB16, MAGEA1, MAGEA10, MAGEA4, MAGEA8, MAGEB17, MAGEB4, MAGEC1, MEK, MLANA, MLL2, MMP13, MSH3, MSH6, MYC, NDUFC2, NRAS
- the modified immune cells further comprise a kill switch (or suicide switch).
- a kill switch or suicide switch
- the kill switch can be activated to eliminate immune cells. This can happen when the immune system reacts so strongly that many inflammatory cytokines are released, causing mild to severe symptoms, including fever, headache, rash, rapid heartbeat, low blood pressure, and difficulty breathing.
- the kill switch may be a drug-induced kill switch.
- the kill switch may comprise inducible caspase-9.
- Various embodiments of the aspects herein include cells, such as modified immune cells.
- Cells such as immune cells (eg, lymphocytes including T cells and NK cells) can be obtained from the subject.
- immune cells eg, lymphocytes including T cells and NK cells
- Non-limiting examples of subjects include humans, dogs, cats, mice, rats and their transgenic species.
- samples from subjects from which cells can be obtained include, but are not limited to, skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gallbladder, colon, intestine, brain, prostate, Esophagus, thyroid, serum, saliva, urine, stomach and digestive juices, tears, feces, semen, vaginal fluid, interstitial fluid from tumor tissue, eye fluid, sweat, mucus, earwax, oil, glandular secretions, spinal cord Fluid, hair, nails, plasma, nasal swab or nasopharyngeal cleansing, spinal fluid, cerebrospinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, umbilical cord blood, strong fluid, cavity fluid, sputum, pus , Microbiota, meconium, breast milk and/or other excreta or body tissues.
- the cells may be T cell populations, NK cells, B cells, etc. obtained from the subject.
- T cells can be obtained from many sources, including PBMC, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, and tissue from infection sites, ascites, pleural effusion, spleen tissue, and tumors.
- any number of techniques such as FicollTM isolation, can be used to obtain T cells from blood units collected from the subject.
- cells from the circulating blood of the individual are obtained by apheresis.
- Apheresis blood component products usually contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells and platelets. The cells collected by apheresis can be washed to remove the plasma fraction and placed in a suitable buffer or medium for subsequent processing steps.
- immune cells include granulocytes, such as asophils, eosinophils, and neutrophils; mast cells; monocytes that can develop into macrophages; antigen-presenting cells, such as dendritic cells; and Lymphocytes, such as natural killer cells (NK cells), B cells and T cells.
- the immune cell is an immune effector cell.
- Immune effector cells refer to immune cells that can perform specific functions in response to stimulation.
- immune cells are immune effector cells that can induce cell death.
- the immune cells are lymphocytes.
- the lymphocytes are NK cells.
- the lymphocytes are T cells.
- the T cell is an activated T cell.
- T cells include naive and memory cells (such as central memory or TCM, effector memory or TEM and effector memory RA or TEMRA), effector cells (such as cytotoxic T cells or CTL or Tc cells), helper cells (such as Th1, Th2, Th3 ), Th9, Th7, TFH), regulatory cells (such as Treg and Tr1 cells), natural killer T cells (NKT cells), tumor infiltrating lymphocytes (TIL), lymphocyte activated killer cells (LAK), ⁇ T cells, ⁇ Similar unique categories of cell and T cell lineages.
- T cells can be divided into two categories: CD8+ T cells and CD4+ T cells, based on the presence of proteins on the cell surface.
- T cells expressing the subject's system can perform a variety of functions, including killing infected cells and activating or recruiting other immune cells.
- CD8+ T cells are called cytotoxic T cells or cytotoxic T lymphocytes (CTL).
- CTL expressing the subject's system can participate in the identification and removal of virus-infected cells and cancer cells.
- CTL has specialized compartments or granules that contain cytotoxins that cause apoptosis, such as programmed cell death.
- CD4+ T cells can be subdivided into four subgroups-Th1, Th2, Th17 and Treg. "Th” refers to "T helper cells", although other subgroups may exist.
- Th1 cells can coordinate the immune response against intracellular microorganisms, especially bacteria.
- Th2 cells can produce and secrete molecules that alert and activate other immune cells, such as bacteria that ingest macrophages.
- Th2 cells are involved in coordinating the immune response against extracellular pathogens such as worms (parasites) by warning B cells, granulocytes and mast cells.
- Th17 cells can produce interleukin 17 (IL-17), a signaling molecule that activates immune and non-immune cells. Th17 cells are important for recruiting neutrophils.
- IL-17 interleukin 17
- the immune cell populations provided herein may be heterogeneous.
- the cells used may consist of a heterogeneous mixture of CD4 and CD8 T cells.
- CD4 and CD8 cells can have the phenotypic characteristics of circulating effector T cells.
- the CD4 and CD8 cells may also have the phenotypic characteristics of effector memory cells.
- the cell may be a central memory cell.
- the cells include peripheral blood mononuclear cells (PBMC), peripheral blood lymphocytes (PBL) and other blood cell subpopulations, such as but not limited to T cells, natural killer cells, monocytes, natural killer T cells , Monocyte precursor cells, hematopoietic stem cells or non-pluripotent stem cells.
- the cell can be any immune cell, including any T cell, such as tumor infiltrating cells (TIL), such as CD3+ T cells, CD4+ T cells, CD8+ T cells, or any other type of T-cells.
- T cells may also include memory T cells, memory stem T cells or effector T cells. T cells can also be selected from a large population (bulk population), for example, T cells are selected from whole blood.
- T cells can also be expanded from large populations. T cells can also be biased towards specific populations and phenotypes. For example, T cells can be biased towards a certain phenotype, including CD45RO(-), CCR7(+), CD45RA(+), CD62L(+), CD27(+), CD28(+) and/or IL-7R ⁇ (+) . Appropriate cells can be selected, which contain one or more markers selected from the following list: CD45RO(-), CCR7(+), CD45RA(+), CD62L(+), CD27(+), CD28(+) ) And/or IL. -7R ⁇ (+).
- Cells also include stem cells, such as embryonic stem cells, induced pluripotent stem cells, hematopoietic stem cells, neuronal stem cells and mesenchymal stem cells.
- the cells may comprise any number of primary cells, such as human cells, non-human cells and/or mouse cells.
- the cell may be a progenitor cell.
- the cells can be derived from the subject to be treated (e.g., patient).
- the cells can be derived from a human donor.
- the host cell can be a stem memory TSCM cell composed of CD45RO(-), CCR7(+), CD45RA(+), CD62L+ (L-selectin), CD27+, CD28+ and IL-7R ⁇ +, and the stem memory cell can also be It expresses CD95, IL-2R ⁇ , CXCR3 and LFA-1, and shows many functional properties different from the stem storage cells.
- the host cell may be a central memory TCM cell containing L-selectin and CCR7, and the central memory cell may secrete, for example, IL-2, but not IFN ⁇ or IL-4.
- the cells can also be effector memory TEM cells containing L-selectin or CCR7, and produce, for example, effector cytokines such as IFN ⁇ and IL-4.
- the immune cells comprise lymphocytes.
- the lymphocytes are natural killer cells (NK cells).
- the lymphocytes are T cells.
- T cells can be obtained from many sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, spleen tissue, umbilical cord and tumors. In some embodiments, any number of available T cell lines can be used.
- Immune cells such as lymphocytes (e.g., cytotoxic lymphocytes) may preferably be autologous cells, but heterologous cells may also be used. Any number of techniques, such as Ficoll separation, can be used to obtain T cells from blood units collected from the subject.
- Cells from the circulating blood of the individual can be obtained by apheresis or leukopenia.
- Apheresis blood component products usually contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells and platelets.
- the cells collected by apheresis can be washed to remove the plasma fraction, and the cells can be placed in a suitable buffer or medium, such as phosphate buffered saline (PBS), for subsequent processing steps. After washing, the cells can be resuspended in various biocompatible buffers, such as Ca-free Mg-free PBS.
- PBS phosphate buffered saline
- the undesired components of the apheresis blood component sample can be removed and the cells can be directly resuspended in the culture medium.
- the sample may be provided directly by the subject or indirectly through one or more intermediates, such as a sample collection service provider or a medical provider (such as a doctor or a nurse).
- separating T cells from peripheral blood leukocytes may include lysing red blood cells and separating them from peripheral blood leukocytes from monocytes by, for example, PERCOLTM gradient centrifugation.
- a specific subset of T cells can be further separated by positive or negative selection techniques.
- negative selection of T cell populations can be achieved.
- One suitable technique includes cell sorting by negative magnetic immunoadhesion, which utilizes a mixture of monoclonal antibodies directed against cell surface markers present on negatively selected cells.
- the monoclonal antibody mixture may include antibodies against CD14, CD20, CD11b, CD16, HLA-DR and CD8.
- the negative selection process can be used to generate a desired population of T cells that is mostly homogeneous.
- the composition comprises a mixture of two or more (eg, 2, 3, 4, 5 or more) different types of T cells.
- immune cells are members of an enriched cell population.
- One or more desired cell types can be enriched by any suitable method, non-limiting examples of which include treatment of cell populations to trigger expansion and/or differentiation into desired cell types, and treatment to prevent the development of unwanted cell types. Growth, treatment to kill or lyse unwanted cell types, purification of desired cell types (e.g., purification on an affinity column to retain desired or unwanted cell types based on one or more cell surface markers).
- the enriched cell population is a cell population rich in cytotoxic lymphocytes selected from cytotoxic T cells (also known as cytotoxic T lymphocytes, CTL, T killer cells, Cytolytic T cells, CD8+ T cells and killer T cells), natural killer (NK) cells and lymphokine activated killer (LAK) cells.
- cytotoxic T cells also known as cytotoxic T lymphocytes, CTL, T killer cells, Cytolytic T cells, CD8+ T cells and killer T cells
- NK natural killer cells
- LAK lymphokine activated killer
- the concentration of cells and surface can be changed.
- it may be necessary to significantly reduce the volume at which the beads and cells are mixed together ie, increase the cell concentration) to ensure maximum contact between the cells and the beads.
- a concentration of 2 billion cells/mL can be used.
- a concentration of 1 billion cells/mL is used.
- more than 100 million cells/mL are used.
- Cell concentrations of 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, or 50 million cells/mL can be used.
- a cell concentration of 75 million, 80 million, 85 million, 90 million, 95 million, or 100 million cells/mL can be used. In further embodiments, a concentration of 125 million or 150 million cells/mL can be used. Using high concentrations can lead to increased cell yield, cell activation and cell expansion.
- Target cells to which this method can be applied include various cell types.
- the target cell can be in vitro.
- the target cell can be in the body.
- the target cell can be ex vivo.
- the target cell may be an isolated cell.
- the target cell may be a cell in an organism.
- the target cell may be an organism.
- the target cell may be a cell in cell culture.
- the target cell may be one of a collection of cells.
- the target cell may be a mammalian cell or derived from a mammalian cell.
- the target cell can be a rodent cell or derived from a rodent cell.
- the target cell may be a human cell or derived from a human cell.
- the target cell may be a prokaryotic cell or derived from a prokaryotic cell.
- the target cell may be a bacterial cell or may be derived from a bacterial cell.
- the target cell may be an archaeal cell or derived from an archaeal cell.
- the target cell can be a eukaryotic cell or derived from a eukaryotic cell.
- the target cell may be a pluripotent stem cell.
- the target cell can be a plant cell or derived from a plant cell.
- the target cell can be an animal cell or derived from an animal cell.
- the target cell can be an invertebrate cell or derived from an invertebrate cell.
- the target cell may be a vertebrate cell or derived from a vertebrate cell.
- the target cell may be a microbial cell or derived from a microbial cell.
- the target cell can be a fungal cell or derived from a fungal cell.
- the target cell can be a stem cell or a progenitor cell.
- Target cells may include stem cells (e.g., adult stem cells, embryonic stem cells, induced pluripotent stem (iPS) cells) and progenitor cells (e.g., cardiac progenitor cells, neural progenitor cells, etc.).
- Target cells may include mammalian stem cells and progenitor cells, including rodent stem cells, rodent progenitor cells, human stem cells, human progenitor cells, and the like.
- the cloned cell may comprise the progeny of the cell.
- the target cell may contain a target nucleic acid.
- the target cell can be in a living organism.
- the target cell may be a genetically modified cell.
- the target cell may be a host cell.
- the target cell may be a primary cell.
- a culture of primary cells can be passaged 0 times, 1 time, 2 times, 4 times, 5 times, 10 times, 15 times or more.
- the cell can be a single cell organism.
- the cells can be grown in medium.
- the target cell may be a diseased cell.
- Diseased cells may have altered metabolism, gene expression, and/or morphological characteristics.
- the diseased cells can be cancer cells, diabetic cells and apoptotic cells.
- the diseased cell may be a cell from a diseased subject.
- Exemplary diseases may include blood disorders, cancer, metabolic disorders, eye diseases, organ disorders, musculoskeletal disorders, heart disease, and the like.
- the target cells can be harvested from the individual by any method.
- leukocytes can be harvested by apheresis, leukocyte removal, density gradient separation, etc.
- Biopsy can be used to harvest cells from tissues such as skin, muscle, bone marrow, spleen, liver, pancreas, lung, intestine, stomach, etc.
- a suitable solution can be used to isolate or suspend the harvested cells.
- This solution can usually be a balanced salt solution (such as physiological saline, phosphate buffered saline (PBS), Hank's balanced salt solution, etc.), conveniently supplemented with fetal bovine serum or other naturally occurring factors, and an acceptable low concentration of buffer .
- PBS phosphate buffered saline
- Hank's balanced salt solution etc.
- the buffer may include HEPES, phosphate buffer, lactate buffer and the like.
- the cells can be used immediately, or they can be stored (for example by freezing). Frozen cells can be thawed and can be reused. Cells can be frozen in DMSO, serum, medium buffer (for example, 10% DMSO, 50% serum, 40% buffer medium) and/or some other such common solutions for preservation of cells at freezing temperatures.
- Non-limiting examples of cells that can be target cells include, but are not limited to, lymphocytes, such as B cells, T cells (cytotoxic T cells, natural killer T cells, regulatory T cells, T helper cells), natural killer cells, cells Factor-induced killer cell (CIK) cells (see, for example, US20080241194); bone marrow cells, such as granulocytes (basophils, eosinophils, neutrophils/excessive neutrophils), monocytes/macro Phage cells, red blood cells (reticulocytes), mast cells, platelets/megakaryocytes, dendritic cells; cells from the endocrine system, including thyroid (thyroid epithelial cells, parafollicular cells), parathyroid (parathyroid master cells) , Oxyphil cells), adrenal glands (chromaffin cells), pineal (pineal cells) cells; nervous system cells, including glial cells (astrocytes, microglia), giant cell neurosecretory cells , Stellate cells, Boettcher
- the target cell is a cancer cell.
- cancer cells include cancer cells, including acanthoma, Acinic cell carcinoma, acoustic neuroma, Acral lentiginous melanoma, Acrospiroma, acute eosinophilic leukemia, acute lymphocytic leukemia, acute megakaryocyte leukemia, acute mononuclear cell Leukemia, mature acute myeloblastic leukemia, acute myeloid dendritic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, diamond disease, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoma-like teeth Source tumors, adrenal cortical carcinoma, adult T-cell leukemia, aggressive NK-cell leukemia, AIDS-related cancer, AIDS-related lymphoma, alveolar soft tissue sarcoma, ameloblastoma, an
- targeted cancer cells represent a subpopulation of a population of cancer cells, such as cancer stem cells.
- the cancer is of a hematopoietic lineage, such as lymphoma.
- the antigen may be a tumor-associated antigen.
- the target cell forms a tumor.
- Tumors treated by the methods herein can result in stable tumor growth (e.g., the volume of one or more tumors does not increase by more than 1%, 5%, 10%, 15%, or 20%, and/or does not metastasize).
- the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks.
- the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months.
- the tumor is stable for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years.
- the size of the tumor or the number of tumor cells is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more.
- the tumor is completely eliminated, or reduced to below the detection level.
- the subject remains tumor-free (eg, in remission) for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more weeks after treatment.
- the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months after treatment.
- the subject remains tumor-free for at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years after treatment.
- the death of target cells can be determined by any suitable method, including but not limited to counting cells before and after treatment, or measuring the level of markers associated with live or dead cells (eg, live or dead target cells).
- the degree of cell death can be determined by any suitable method. In some embodiments, the degree of cell death is determined relative to the starting conditions. For example, an individual may have a known starting amount of target cells, such as a starting cell mass of a known size or a known concentration of circulating target cells. In this case, the degree of cell death can be expressed as the ratio of surviving cells to the starting cell population after treatment. In some embodiments, the degree of cell death can be determined by a suitable cell death assay. Various cell death analyses can be used, and multiple detection methods can be used. Examples of detection methods include, but are not limited to, cell staining, microscopy, flow cytometry, cell sorting, and the use of combinations of these.
- the efficacy of the treatment in reducing tumor size can be determined by measuring the percentage of necrotic (ie, dead) resected tissue. In some embodiments, if the percentage of necrosis of the resected tissue is greater than about 20% (eg, at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, the treatment is effective). Or 100%). In some embodiments, the percentage of necrosis of the resected tissue is 100%, that is, no viable tumor tissue is present or detectable.
- Exposure of target cells to the immune cells or populations of immune cells disclosed herein can be performed in vitro or in vivo. Exposing target cells to immune cells or immune cell populations generally refers to bringing the target cells into contact with the immune cells and/or close enough so that the target cell's antigen or membrane protein (for example, membrane-bound or non-membrane-bound) can be expressed in the immune cell Enhance receptor or CAR or TCR binding. Exposing a target cell to an immune cell or immune cell population also generally refers to bringing the target cell into contact with the immune cell and/or close enough so that the target cell can bind to the non-specific killing immune cell. By co-culturing target cells and immune cells, immune cells or immune cell populations can be exposed to target cells in vitro.
- Target cells and immune cells can be co-cultured, for example, as adherent cells or as a suspension.
- Target cells and immune cells can be co-cultured in various types of cell culture media, such as supplements, growth factors, ions, and the like.
- Target cells can be exposed to immune cells or populations of immune cells in vivo, in some cases by administering immune cells to a subject (e.g., a human subject), and allowing immune cells to localize to the target cells through the circulatory system.
- immune cells can be delivered to the direct area where the target cells are located, for example by direct injection.
- the exposure can be carried out for any suitable length of time, for example at least 1 minute, at least 5 minutes, at least 10 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, At least 7 hours, at least 8 hours, at least 12 hours, at least 16 hours, at least 20 hours, at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 1 week, at least 2 Weeks, at least 3 weeks, at least 1 month or more.
- the various domains of the enhanced receptor and CAR provided herein can be linked by chemical bonds, such as amide bonds or disulfide bonds; a small organic molecule (such as a hydrocarbon chain); amino acid sequences, such as peptide linkers (such as a length of about 3 -200 amino acid sequence), or a combination of small organic molecules and peptide linkers.
- the peptide linker can provide the required flexibility to allow the desired expression, activity and/or conformational positioning of the chimeric polypeptide.
- the peptide linker can have any suitable length to connect at least two domains of interest, and is preferably designed to be flexible enough to allow the correct folding and/or function and/or activity of the one or two domains to which it is connected.
- the peptide linker may have a length of at least 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 Amino acids. In some embodiments, the length of the peptide linker is about 0 to 200 amino acids, about 10 to 190 amino acids, about 20 to 180 amino acids, about 30 to 170 amino acids, about 40 to 160 amino acids, about 50 to 150 Amino acids, about 60 to 140 amino acids, about 70 to 130 amino acids, about 80 to 120 amino acids, about 90 to 110 amino acids.
- the linker sequence may comprise an endogenous protein sequence. In some embodiments, the linker sequence comprises glycine, alanine and/or serine amino acid residues.
- the linker may contain a motif of GS, GGS, GGGGS, GGSG, or SGGG, such as multiple or repeated motifs.
- the linker sequence may include any naturally occurring amino acid, non-naturally occurring amino acid, or a combination thereof.
- compositions and molecules of the present disclosure e.g., polypeptides and/or nucleic acids encoding polypeptides
- host cells such as immune cells.
- the various components can be delivered simultaneously or separated in time. The choice of method may depend on the type of transformed cell and/or the environment in which the transformation occurs (e.g., in vitro, ex vivo, or in vivo).
- the delivery method may include contacting a target polynucleotide or introducing one or more nucleic acids into a cell (or cell population such as immune cells), the nucleic acid comprising a nucleotide sequence encoding a composition of the invention.
- a suitable nucleic acid comprising a nucleotide sequence encoding a composition of the present disclosure may include an expression vector, wherein the expression vector comprising a nucleotide sequence encoding one or more compositions of the present disclosure is a recombinant expression vector.
- Non-limiting examples of delivery methods or transformations include, for example, viral or phage infection, transfection, conjugation, protoplast fusion, lipofection, electroporation, calcium phosphate precipitation, polyethyleneimine (PEI) mediated Transfection, DEAE-dextran-mediated transfection, liposome-mediated transfection, particle gun technology, calcium phosphate precipitation, direct microinjection and nanoparticle-mediated nucleic acid delivery.
- delivery methods or transformations include, for example, viral or phage infection, transfection, conjugation, protoplast fusion, lipofection, electroporation, calcium phosphate precipitation, polyethyleneimine (PEI) mediated Transfection, DEAE-dextran-mediated transfection, liposome-mediated transfection, particle gun technology, calcium phosphate precipitation, direct microinjection and nanoparticle-mediated nucleic acid delivery.
- PEI polyethyleneimine
- the present disclosure provides methods that include combining one or more polynucleotides, or one or more vectors as described herein, or one or more transcripts thereof, and/or a transcribed Methods of delivering one or more proteins to host cells.
- the present disclosure also provides cells produced by these methods, and organisms (such as animals, plants, or fungi) that contain these cells or are produced by these cells.
- Non-viral vector delivery systems can include DNA plasmids, RNA (for example, transcripts of vectors described herein), naked nucleic acids, and nucleic acids complexed with delivery vehicles, such as liposomes.
- Viral vector delivery systems can include DNA and RNA viruses, which can have episomal or integrated genomes after delivery to cells.
- Non-viral nucleic acid delivery methods can include lipofection, nucleofection, microinjection, bioprojectile, virosome, liposome, immunoliposome, polycation or lipid: nucleic acid conjugate, naked DNA , Artificial virus particles and DNA agents enhance uptake. Efficient receptors suitable for polynucleotides can be used to recognize lipofected cationic and neutral lipids. Delivery can be cellular (e.g. in vitro or ex vivo administration) or target tissue (e.g. in vivo administration). The preparation of lipids can be used: nucleic acid complexes, including targeted liposomes, such as immunolipid complexes.
- RNA or DNA virus-based systems can be used to target specific cells in the body and transport the viral payload to the nucleus.
- Viral vectors can be administered directly (in vivo), or they can be used to treat cells in vitro, and can optionally be administered to modified cells (ex vivo).
- Virus-based systems may include retrovirus, lentivirus, adenovirus, adeno-associated and herpes simplex virus vectors for gene transfer. Using retrovirus, lentivirus and adeno-associated virus gene transfer methods can be integrated in the host genome, which can lead to long-term expression of the inserted transgene. High transduction efficiency can be observed in many different cell types and target tissues.
- Lentivirus can integrate its genome into host cells (such as 293 cells, or T cells). Lentivirus can use a three-plasmid system or a four-plasmid system.
- Lentiviral vectors are retroviral vectors that can transduce or infect non-dividing cells and produce high viral titers.
- the choice of retroviral gene transfer system can depend on the target tissue.
- Retroviral vectors can contain cis-acting long terminal repeats, which have packaging capabilities of up to 6-10 kb of foreign sequence.
- Minimal cis-acting LTR can be sufficient for vector replication and packaging, which can be used to integrate therapeutic genes into target cells to provide permanent transgene expression.
- Retroviral vectors may include vectors based on murine leukemia virus (MuLV), gibbon leukemia virus (GaLV), simian immunodeficiency virus (SIV), human immunodeficiency virus (HIV), and combinations thereof.
- Adenovirus-based systems can be used. Adenovirus-based systems can lead to transient expression of transgenes. Adenovirus-based vectors can have high transduction efficiency in cells and may not require cell division. High titers and expression levels can be obtained with adenovirus-based vectors.
- Adeno-associated virus (“AAV") vectors can be used to transduce cells with target nucleic acids, for example, to produce nucleic acids and peptides in vitro, and for in vivo and ex vivo gene therapy procedures.
- Packaging cells can be used to form viral particles capable of infecting host cells.
- Such cells may include 293 cells (for example, for packaging lentivirus or adenovirus) and Psi2 cells or PA317 cells (for example, for packaging retrovirus).
- Viral vectors can be produced by generating cell lines that package nucleic acid vectors into viral particles.
- the vector may contain the minimal viral sequences required for packaging and subsequent integration into the host.
- the vector may contain other viral sequences, which are replaced by the expression cassette of the polynucleotide to be expressed.
- the missing viral functions can be provided in trans by the packaging cell line.
- an AAV vector may contain an ITR sequence from the AAV genome, which is necessary for packaging and integration into the host genome.
- Viral DNA can be packaged in a cell line that contains helper plasmids encoding other AAV genes, namely rep and cap, but lacks the ITR sequence.
- Cell lines can also be infected with adenovirus as a helper cell.
- the helper virus can promote the replication of the AAV vector and the expression of the AAV gene from the helper plasmid. Contamination of adenovirus can be reduced by, for example, heat treatment in which adenovirus is more sensitive than AAV.
- Other methods for delivering nucleic acids to cells can be used, for example, as described in US20030087817, which is incorporated herein by reference.
- the host cell can be transfected transiently or non-transiently with one or more of the vectors described herein.
- the cell can be transfected because it is naturally present in the subject.
- the cells can be taken or derived from the subject and transfected.
- the cells may be derived from cells taken from the subject, such as cell lines.
- cells transfected with one or more of the vectors described herein are used to establish new cell lines containing one or more vector-derived sequences.
- cells transiently transfected with the composition of the present disclosure e.g., by transient transfection of one or more vectors, or transfected with RNA
- vectors for eukaryotic host cells include pXT1, pSG5 (StratageneTM), pSVK3, pBPV, pMSG, and pSVLSV40 (PharmaciaTM).
- the cells can be suspended in any convenient appropriate nutrient medium, such as Iscove's modified DMEM or RPMI 1640, supplemented with fetal bovine serum or heat-inactivated goat serum (about 5-10%), L-glutamine , Mercaptans, especially 2-mercaptoethanol and antibiotics, such as penicillin and streptomycin.
- the culture may contain growth factors to which the cells respond. Growth factors as defined herein are molecules capable of promoting the survival, growth and/or differentiation of cells in culture or intact tissues through specific effects on transmembrane receptors. Growth factors can include polypeptide and non-polypeptide factors.
- the selected delivery system targets a specific tissue or cell type.
- tissue or cell targeting of the delivery system is achieved by combining the delivery system with tissue or cell-specific markers (e.g., cell surface proteins).
- tissue or cell-specific markers e.g., cell surface proteins.
- Viral and non-viral delivery systems can be customized to target tissues or cell types of interest.
- compositions containing the molecules described herein (for example, polypeptides and/or nucleic acids or proteins encoding polypeptides) or immune cells can be administered for prophylactic and/or therapeutic treatments.
- the composition can be administered to a subject already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent the symptoms of the disease or condition, or to cure, heal, improve or improve the condition.
- the amount effective for this purpose can vary depending on the severity and course of the disease or condition, previous treatment, the subject's health, weight and response to the drug, and the judgment of the treating physician.
- the multiple therapeutic agents can be administered in any order or simultaneously. If at the same time, multiple therapeutic agents can be provided in a single, unified form or in multiple forms, for example, as multiple separate pills or cell solutions.
- the molecule or cell solution can be packaged together or separately in a single package or in multiple packages.
- One or all therapeutic agents can be given in multiple doses. If not at the same time, the time between multiple doses can vary to about 1 to 24 months.
- the molecules or cells described herein can be administered before, during, or after the onset of the disease or condition, and the time of administration of the compound-containing composition can vary.
- the pharmaceutical composition can be used as a preventive agent, and can be continuously administered to a subject who has a disease or disease tendency to prevent the occurrence of the disease or disease.
- the molecules, cells, and pharmaceutical compositions can be administered to the subject during the onset of symptoms or as soon as possible.
- the administration of the molecule can be initiated within the first 48 hours of the onset of symptoms, within the first 24 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within 3 hours of the onset of symptoms.
- the initial administration can be by any practical route, for example, by using any of the formulations described herein.
- the molecule can be administered as soon as feasible after the onset of a disease or condition is detected or suspected, and the length of time required to treat the disease, for example, from about 1 month to about 3 months. The duration of treatment for each subject may be
- the molecules can be packaged into biological compartments.
- the biological compartment containing the molecule can be administered to the subject.
- Biological compartments can include but are not limited to viruses (lentivirus, adenovirus), nanospheres, liposomes, quantum dots, nanoparticles, microparticles, nanocapsules, vesicles, polyethylene glycol particles, hydrogels and micelles .
- the biological compartment may contain liposomes.
- the liposome may be a self-assembled structure containing one or more lipid bilayers, and each lipid bilayer may contain two monolayers containing amphiphilic lipid molecules in opposite orientations.
- Amphiphilic lipids may comprise a polar (hydrophilic) head group covalently linked to one or two or more non-polar (hydrophobic) acyl or alkyl chains.
- the energetically unfavorable contact between the hydrophobic acyl chain and the surrounding aqueous medium induces the amphiphilic lipid molecules to align themselves, so that the polar head group can be oriented toward the surface of the bilayer, and the acyl chain is oriented toward the interior of the bilayer, effectively shielding the acyl The chain is not in contact with the water environment.
- the liposomes may include glycerol phosphate and sphingolipids.
- Representative examples include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylglycerol, and palmitoyl oil.
- DMPC dimyristoyl lecithin
- DPPC example dipalmitoyl lecithin
- dioleoyl phosphatidyl choline Alkali distearoylphosphatidylcholine (DSPC), dilinoleylphosphatidylcholine and sphingomyelin, or any combination thereof.
- the biological compartment may contain nanoparticles.
- the diameter of the nanoparticles may be about 40 nanometers to about 1.5 micrometers, about 50 nanometers to about 1.2 micrometers, about 60 nanometers to about 1 micrometer, about 70 nanometers to about 800 nanometers, about 80 nanometers.
- the release rate can be slowed or prolonged, and as the size of the nanoparticle decreases, the release rate can be increased.
- the amount of albumin in the nanoparticle can be about 5% to about 85% albumin (v/v), about 10% to about 80%, about 15% to about 80%, about 20% to about 20%. About 70% albumin (v/v), about 25% to about 60%, about 30% to about 50%, or about 35% to about 40%.
- the pharmaceutical composition may contain up to 30, 40, 50, 60, 70 or 80% or more nanoparticles.
- the nucleic acid molecules of the present disclosure can be bound to the surface of the nanoparticle.
- the biological compartment may contain viruses.
- the virus may be the delivery system of the pharmaceutical composition of the present disclosure.
- Exemplary viruses may include lentivirus, retrovirus, adenovirus, herpes simplex virus I or II, parvovirus, reticuloendothelioma virus, and adeno-associated virus (AAV).
- a virus can be used to deliver the pharmaceutical composition of the present disclosure to a cell.
- Viruses can infect and transduce cells in vivo, ex vivo or in vitro. In ex vivo and in vitro delivery, the transduced cells can be administered to a subject in need of treatment.
- the pharmaceutical composition can be packaged into a viral delivery system.
- the composition can be packaged into viral particles by the HSV-1 helper-free virus packaging system.
- the virus delivery system (for example, the virus containing the pharmaceutical composition of the present disclosure) can be through direct injection, stereotactic injection, intracerebroventricular, via a micropump infusion system, via convection, catheter, intravenous, parenteral, intraperitoneal and/ Or subcutaneous injection for administration. Inject into the cells, tissues or organs of the subject in need. In some cases, cells can be transduced with a viral delivery system in vitro or ex vivo. The transduced cells can be administered to a subject suffering from a disease. For example, a viral delivery system containing a pharmaceutical composition can be used to transduce stem cells, and the stem cells can be implanted in a patient to treat diseases.
- the dose of cells administered to the subject may be less than 1 ⁇ 10 4 cells/kg, or about 1 ⁇ 10 4 cells/kg, about 2 ⁇ 10 4 cells/kg, about 3 ⁇ 10 4 cells/kg, about 4 ⁇ 10 4 cells/kg, about 5 ⁇ 10 4 cells/kg, about 6 ⁇ 10 4 cells/kg, about 7 ⁇ 10 4 cells/kg, about 8 ⁇ 10 4 cells/kg, about 9 ⁇ 10 4 cells, about 1 ⁇ 10 5 cells/kg, about 2 ⁇ 10 5 cells/kg, about 3 ⁇ 10 5 cells/kg, about 4 ⁇ 10 5 cells /kg, about 5 ⁇ 10 5 cells/kg, about 6 ⁇ 10 5 cells/kg, about 7 ⁇ 10 5 cells/kg, about 8 ⁇ 10 5 cells/kg, about 9 ⁇ 10 5 cells , About 1 ⁇ 10 6 cells/kg, about 2 ⁇ 10 6 cells/kg, about 3 ⁇ 10 6 cells/kg, about 4 ⁇ 10 6 cells/kg, about 5 ⁇ 10 6 cells/kg, About 6 ⁇ 10 6 cells/kg, about 7 ⁇ 10 6 cells/kg, about 8 ⁇ 10 6 cells/kg, about
- Biological compartments can be introduced into cells by the following methods: virus or phage infection, transfection, conjugation, protoplast fusion, lipofection, electroporation, calcium phosphate precipitation, polyethyleneimine (PEI)-mediated transduction Transfection, DEAE-dextran-mediated transfection, liposome-mediated transfection, particle gun technology, calcium phosphate precipitation, direct microinjection, nanoparticle-mediated nucleic acid delivery, etc.
- PEI polyethyleneimine
- immune cells expressing the subject's system are administered.
- Immune cells expressing the subject's system can be administered before, during or after the occurrence of the disease or condition, and the timing of administration of the immune cells can vary.
- immune cells expressing the subject's system can be used as a preventive agent, and can be continuously administered to a subject with a disorder or disease tendency to prevent the occurrence of the disease or disorder.
- Immune cells can be administered to the subject during the onset of symptoms or as soon as possible. The administration can be started within the first 48 hours of the onset of symptoms, within the first 24 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within the first 3 hours of the onset of symptoms.
- the initial administration can be by any suitable route, for example, by using any of the formulations described herein.
- immune cells can be administered as soon as feasible, and treatment of the disease takes a period of time, for example, about 1 month to about 3 months. The duration of treatment for each subject may be different.
- the molecules (e.g., polypeptides and/or nucleic acids) described herein may be present in the composition in the range of about 1 mg to about 2000 mg, about 5 mg to about 1000 mg, about 10 mg to about 25 mg to 500 mg, about 50 mg to about 250 mg, About 100 mg to about 200 mg, about 1 mg to about 50 mg, about 1 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 300 mg To about 350mg, about 350mg to about 400mg, about 400mg to about 450mg, about 450mg to about 500mg, about 500mg to about 550mg, about 550mg to about 600mg, about 600mg to about 650mg, about 650mg to about 700mg, about 700mg to About 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg
- the molecules (eg, polypeptides and/or nucleic acids) described herein may be present in the composition in amounts of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg , About 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 650mg, about 700mg, about 750mg, about 800mg, about 850mg, about 900mg, About 950 mg, about 1000 mg, about 1050 mg,
- the molecules (e.g., polypeptides and/or nucleic acids) described herein may be present in each mg providing at least 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 10 Or more units of active molecules in the composition.
- This activity can be the regulation of gene expression.
- the total number of active units of molecules delivered to the subject is at least 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 60,000, 70,000, 80,000, 90,000, 110,000, 120,000, 130,000, 140,000, 150,000, 160,000 , 170,000, 180,000, 190,000, 200,000, 210,000, 220,000, 230,000 or 250,000 or more units.
- the total number of active units of molecules delivered to the subject is at most 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 60,000, 70,000, 80,000, 90,000, 110,000, 120,000, 130,000, 140,000, 150,000, 160,000 , 170,000, 180,000, 190,000, 200,000, 210,000, 220,000, 230,000 or 250,000 or more units.
- CD19 as the booster antigen
- CAR targeting CD19 for the sequence of the CAR used, please refer to SEQ ID NO:1 in CN 110016465A) as aBA-CAR.
- Human CAR-T cells were prepared as follows: After collecting human PBMC cells, CD3/CD28 magnetic beads were used to activate T cells in CD19 - cells derived from PBMC and transfected with CD19-CAR lentivirus.
- Human super TIL cells are prepared as follows: After collecting monocytes from patients with advanced tumors, magnetic beads are used to capture PD1+ T cells. A lentiviral vector containing the following two coding sequences was constructed: the nucleotide sequence encoding CD19CAR as aBA-CAR, and the nucleotide sequence encoding the enhanced receptor-PD1-CD28. The constructed lentivirus was used to transfect the captured PD1+ T cells.
- Example 2 Boosting adjuvant 1-Autologous B cells boosting super TIL expansion
- B cells from the apheresis cells of patients and culture them to the order of 10 7 cells. B cells naturally carry CD19 membrane antigen as a booster antigen.
- the super TIL cells prepared as in Example 1 were divided into two groups AB, each on the order of 10 6 cells.
- Group A allowed its natural growth as a control, and group B was treated as follows.
- the order of magnitude of 106 B cells with autologous TIL cells super order of 106 co-cultured for 10 days as one, each one order of magnitude increase in 106 autologous B cells in the system, three continuous culture. It can be observed that each round of Super TIL has increased by more than 5 times compared to the previous round, while the number of Super TIL in the control group A did not increase significantly.
- Isolate T cells from apheresis cells of the patient transfect the isolated T cells with a lentivirus loaded with CD19 coding sequence, obtain CD19+ T cells as booster cells, and culture the cells to 10 7 with CD3/CD28 magnetic beads stimulation Magnitude.
- the super TIL cells were divided into two groups AB, each of the order of 10 6 cells, group A allowed its natural growth as a control; group B was treated as follows.
- group A allowed its natural growth as a control;
- group B was treated as follows.
- Example 4 Boosting adjuvant 3-Patient's autologous NK cells boosting super TIL expansion
- Isolate NK cells from apheresis cells of patients transfect the isolated NK cells with a lentivirus loaded with CD19 coding sequence, obtain autologous CD19+ NK cells as booster cells, and culture the cells to 10 with CD3/CD28 magnetic beads stimulation 7 orders of magnitude.
- the super TIL cells were divided into two groups AB, each of the order of 10 6 cells, group A allowed its natural growth as a control; group B was treated as follows.
- group A allowed its natural growth as a control;
- group B was treated as follows.
- Another subject of the volunteer subjects differs from the number of B-cell culture 107.
- B cells naturally carry CD19 membrane antigen as a booster antigen.
- the super TIL cells were divided into two groups AB, each of the order of 10 6 cells, group A allowed its natural growth as a control; group B was treated as follows.
- Example 6 Boosting adjuvant 5-allogeneic NK cells boosting super TIL expansion
- the super TIL cells were divided into two groups AB, each of the order of 10 6 cells, group A allowed its natural growth as a control; group B was treated as follows.
- Example 7 Boosting adjuvant 6-Nanoparticles carrying booster antigens boosting super TIL amplification
- the super TIL cells were divided into two groups AB, each of the order of 10 6 cells, group A allowed its natural growth as a control; group B was treated as follows.
- the total amount of CD19 protein loading of about 1 [mu] g of nanoparticles 106 with the order of the super TIL cells co-cultured, 7 days a, an increase in the system per the total amount of CD19 protein in a total load of approximately 1 g
- the nanoparticles are cultured continuously for 3 rounds. It can be observed that each round of Super TIL has increased by more than 5 times compared to the previous round, while the number of Super TIL in the control group A did not increase significantly.
- First-level booster cells T cells are transfected with a lentivirus loaded with EGFRviii coding sequence to obtain EGFRviii + T cells as booster cells, and the cells are cultured to the order of 10 7 with CD3/CD28 magnetic beads.
- Second-level booster cells T cells are transfected with a lentivirus loaded with both the CD19 coding sequence and the EGFRviii CAR coding sequence (the coding nucleotide sequence is shown in SEQ ID NO:1) to obtain CD19 + EGFRviii-CAR-T cells were stimulated and cultured with CD3/CD28 magnetic beads to the order of 10 7 .
- the super TIL cells were divided into three groups of ABC, each on the order of 10 6 cells.
- Group A allowed its natural growth as a control;
- Group B and Group C were treated as follows.
- the magnitude 106 of the second stage boost cells (C D19 + EGFRviii-CAR- T cells) co-cultured with TIL super, a single-stage boost cells as a positive control.
- 106 is about two orders of magnitude of boost cells 106 with the super order of TIL cells co-cultured for 10 days as one, two boost increase for each one of the cells 106 in the system, three continuous culture.
- Example 9 The secondary boosting system of allogeneic NK+ autologous T cells, boosting the expansion of super TIL
- First-level booster cells Transfect allogeneic NK cells with a lentivirus loaded with EGFRviii coding sequence to obtain EGFRviii + NK cells as booster cells. Use CD3/CD28 magnetic beads to stimulate and culture the cells to the order of 10 7 .
- Second-level booster cells autologous T cells were transfected with a lentivirus loaded with both the CD19 coding sequence and the EGFRviii CAR coding sequence (SEQ ID NO:1) to obtain CD19 + EGFRviii-CAR-T cells, The cells were cultured to the order of 10 7 with CD3/CD28 magnetic beads.
- the super TIL cells were divided into three groups of ABC, each of 10 6 orders of magnitude, and group A allowed its natural growth as a control.
- Group B treated as follows: The co-cultured with TIL 106 super order of the second stage boost cells (CD19 + EGFRviii-CAR-T cells), as a single-stage boost cells used as a positive control.
- 106 is about two orders of magnitude of boost cells 106 with the super order of TIL cells co-cultured for 10 days as one, one for each increase of two orders of magnitude 106 boost cells in the system, three continuous culture.
- Group C treated as follows: After the first stage boost cells (EGFRviii + NK cells) and the second stage boost cells (CD19 + EGFRviii-CAR-T cells) were co-cultured for 10 days, the order of addition of 106 super TIL cells, was added while the first stage boost cell 106 orders of magnitude, in the super of TIL cocultured this environment, as a 10 days, the order of addition of 106 of the first stage boost cells every 10 days, a total of three cultures.
- Example 10 Comparison of B cells and two artificial booster cells whose booster antigens are CD19-CD86 boost CAR-T cells Amplified effect
- This example compares the booster expansion effects of three booster cells on specific immune cells—CAR-T cells targeting CD19.
- the three booster cells are: 1) CD19-expressing natural B cells; 2) The booster antigen is a combination of CD19 and CD86, and the booster cell is an artificial booster cell (abbreviated as T/CD19-86); and 3) the booster antigen is a combination of CD19 and CD86 and the booster cell is K562 cells Artificial booster cells (abbreviated as K562/CD19-86).
- step 2) Transfect the T cells in step 2) with the lentivirus loaded with CD19-CAR;
- step 2) Transfect the T cells in step 2) with the lentivirus loaded with CD19-CD86;
- Example 11 Comparison of booster antigens. Artificial booster cells of a composition comprising EGFRviii boost two CAR-T amplifications Effect of
- composition containing EGFRviii is a composition of EGFRviiit (truncated EGFRviii with the intracellular segment removed), CD86, CD137L, and mbIL15-IL15Ra, the artificial booster cell is K562, and the cell expressing the composition is K562/EGFRviiit Said.
- the two types of immune cells that have been boosted are: 1) CAR-T cells targeting EGFRviii (expressed as EGFRviii-CAR-T); and 2) CAR-T cells targeting EGFRviii with increased PD1-CD28 enhancement Body modification (expressed as EGFRviii-ECAR-T).
- PBMC treated with CD3/CD28 magnetic beads were transfected with the three prepared lentiviruses
- the number of CAR-T cells increased by 21.8 times.
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Abstract
本发明提供了一种可助推免疫细胞在体内的数量扩增的佐剂,以及包含该佐剂和免疫细胞的组合。本发明还提供包含所述佐剂和经修饰的免疫细胞的级联放大助推体系。本发明还提供使用本发明的佐剂和免疫细胞的治疗方法。
Description
本发明属于生物医药技术领域,具体而言本发明提供了一种助推佐剂,可以助推T细胞等免疫细胞在体内实现人工相对可控的数量扩增,从而提升免疫治疗的效果。
实体瘤的免疫细胞治疗的第一个难点在于,患者自体天然T细胞中识别肿瘤的细胞非常少,这导致将肿瘤识别性T细胞从自体天然T细胞中分离出来变得非常困难。其次,即便能够成功分离,要在体外扩增到能够对抗晚期肿瘤并产生显著疗效所需的数量又是非常难的过程。再进一步,即便在体外扩增到所需的数量,这个过程的周期之长、成本之高都对产业化形成挑战。另外,有很多肿瘤识别性T细胞已处于耗竭状态,经过体外扩增后会大量死亡,无法发挥预期的效果。如何改善细胞免疫治疗中使用的免疫细胞的功能,从而实现更好的治疗效果是一个尚待解决的问题。
发明内容
本发明提供了一种免疫细胞治疗的助推佐剂,将其与经过相应修饰的免疫细胞联用时,所述助推佐剂可以助推该免疫细胞在体内的扩增,使得扩增数量大幅提高,从而增强免疫治疗的效果,由此解决了上述问题。
除非另有说明,否则本文公开的一些方法的实践采用免疫学,生物化学,化学,分子生物学,微生物学,细胞生物学,基因组学和重组DNA的常规技术,这些技术在本领域的技术范围内。参见例如Sambrook和Green,Molecular Cloning:A Laboratory Manual,4th Edition(2012);系列分子生物学(F.M.Ausubel等编);系列方法在酶学(Academic Press,Inc.),PCR 2:A Practical Approach(M.J.Machersrs,B.D.Hames and G.R.Taylor编(1995)),Harlow and Lane编(1988)Antibodies,A Laboratory Manual,和Culture of Animal Cells:A Manual of Basic Technique and Specialized Applications,第6版(R.I.Breshney编(2010))。
术语“约”或“近似”意指在本领域普通技术人员确定的特定值的可接受误差范围内,这将部分取决于如何测量或确定该值,即,测量系统的局限性。例如,根据本领域的实践,“约”可以表示在1或大于1的标准偏差内。或者,“约”可表示给定值的最多20%,最多10%,最多5%或最多1%的范围。或者,特别是对于生物系统或过程,该术语可以表示数值的一个数量级,优选地在5倍内,更优选地在2倍内。在申请和权利要求中描述特 定值的情况下,除非另有说明,否则应当假定术语“约”意味着在特定值的可接受误差范围内。
如本文所用,“细胞”通常可指生物细胞。细胞可以是生物体的基本结构,功能和/或生物单元。细胞可以源自具有一种或多种细胞的任何生物。一些非限制性实例包括:原核细胞,真核细胞,细菌细胞,古细菌细胞,单细胞真核生物细胞,原生动物细胞,来自植物的细胞,藻类细胞,真菌细胞,动物细胞,包括来自无脊椎动物的细胞(例如果蝇,刺胞动物,棘皮动物,线虫等),来自脊椎动物的细胞(例如,鱼类,两栖动物,爬行动物,鸟类,哺乳动物)来自哺乳动物的细胞(例如,猪,牛,山羊,绵羊,啮齿动物,大鼠,小鼠,人类等),等等。有时细胞不是源自天然生物(例如细胞可以是合成的,有时称为人造细胞)。
如本文所用的术语“抗原”是指能够被选择性结合剂结合的分子或其片段。例如,抗原可以是可以被选择性结合剂如受体结合的配体。作为另一个例子,抗原可以是抗原分子,其可以被选择性结合剂如免疫蛋白(例如抗体)结合。抗原还可以指能够在动物中使用以产生能够结合该抗原的抗体的分子或其片段。
如本文所用,术语“新抗原”通常是指由基因突变引起的肿瘤特异性抗原。得到的突变蛋白或其片段可以引发抗肿瘤T细胞应答。
如本文所用的术语“基因”是指核酸(例如DNA,例如基因组DNA和cDNA)及其相应的编码RNA转录物的核苷酸序列。如本文所用,关于基因组DNA的术语包括插入的非编码区以及调节区,并且可包括5'和3'末端。在一些用途中,该术语包括转录序列,包括5'和3'非翻译区(5'-UTR和3'-UTR),外显子和内含子。在一些基因中,转录区域将包含编码多肽的“开放阅读框”。在该术语的一些用途中,“基因”仅包含编码多肽所必需的编码序列(例如,“开放阅读框”或“编码区”)。在一些情况下,基因不编码多肽,例如核糖体RNA基因(rRNA)和转移RNA(tRNA)基因。在一些情况下,术语“基因”不仅包括转录序列,而且还包括非转录区域,包括上游和下游调节区,增强子和启动子。基因可以指生物基因组中其天然位置中的“内源基因”或天然基因。基因可以指“外源基因”或非天然基因。非天然基因可以指通常不在宿主生物体中发现但通过基因转移引入宿主生物体的基因。非天然基因也可以指不在生物体基因组中的天然位置的基因。非天然基因还可以指天然存在的核酸或多肽序列,其包含突变,插入和/或缺失(例如,非天然序列)。
如本文所用的术语“抗体”是指具有免疫球蛋白样功能的蛋白质结合分子。术语抗体包括抗体(例如,单克隆和多克隆抗体),以及其衍生物,变体和片段。抗体包括但不限于不同类别(即IgA,IgG,IgM,IgD和IgE)和亚类(例如IgG
1,IgG
2等)的免疫球蛋白(Ig)。 其衍生物,变体或片段可以指保留相应抗体的结合特异性(例如,完整和/或部分)的功能衍生物或片段。抗原结合片段包括Fab,Fab',F(ab')2,可变片段(Fv),单链可变片段(scFv),微抗体,双抗体和单结构域抗体(“sdAb”或“纳米抗体”或“骆驼化抗体”)。术语抗体包括已经优化、工程化或化学缀合的抗体和抗体的抗原结合片段。已经优化的抗体的实例包括亲和力成熟的抗体。已经改造的抗体的实例包括Fc优化的抗体(例如,片段可结晶区域经过优化的抗体)和多特异性抗体(例如,双特异性抗体)。
如本文所用的术语“核苷酸”通常是指碱-糖-磷酸盐组合。核苷酸可包含合成核苷酸。核苷酸可包含合成的核苷酸类似物。核苷酸可以是核酸序列的单体单元(例如脱氧核糖核酸(DNA)和核糖核酸(RNA))。术语核苷酸可包括核糖核苷三磷酸腺苷三磷酸(ATP),尿苷三磷酸(UTP),三磷酸胞嘧啶(CTP),三磷酸鸟苷(GTP)和脱氧核糖核苷三磷酸如dATP,dCTP,dITP,dUTP,dGTP,dTTP或其衍生物。这些衍生物可包括,例如,[αS]dATP,7-脱氮-dGTP和7-脱氮-dATP,以及赋予含有它们的核酸分子核酸酶抗性的核苷酸衍生物。本文使用的术语核苷酸可以指双脱氧核糖核苷三磷酸(ddNTP)及其衍生物。双脱氧核糖核苷三磷酸的说明性实例可包括但不限于ddATP,ddCTP,ddGTP,ddITP和ddTTP。核苷酸可以通过众所周知的技术进行未标记或可检测标记。标记也可以用量子点进行。可检测标记可包括例如放射性同位素,荧光标记,化学发光标记,生物发光标记和酶标记。
术语“多核苷酸”,“寡核苷酸”和“核酸”可互换使用,指任何长度的聚合形式的核苷酸,脱氧核糖核苷酸或核糖核苷酸,或其类似物,可以是单链,双链,或多链形式。多核苷酸对细胞可以是外源的或内源的。多核苷酸可以存在于无细胞环境中。多核苷酸可以是其基因或片段。多核苷酸可以是DNA。多核苷酸可以是RNA。多核苷酸可以具有任何三维结构,并且可以执行已知或未知的任何功能。多核苷酸可包含一种或多种类似物(例如经修饰的主链,糖或核碱基)。
术语“表达”是指多核苷酸从DNA模板转录(例如转录成mRNA或其他RNA转录物)和/或转录的mRNA随后翻译成肽,多肽或蛋白质的一个或多个过程。转录物和编码的多肽可统称为“基因产物”。如果多核苷酸衍生自基因组DNA,则表达可包括在真核细胞中剪接mRNA。针对表达而言,“上调”通常是指相对于其在野生型状态下的表达水平,多核苷酸(例如,RNA,例如mRNA)和/或多肽序列的表达水平增加,而“下调”通常是指相对于其在野生型状态下的表达,多核苷酸(例如,RNA,例如mRNA)和/或多肽序列的表达水平降低。
如本文所用,关于表达或活性的术语“调节”是指改变表达或活性水平。调节可以在转录水平和/或翻译水平发生。
术语“肽”,“多肽”和“蛋白质”在本文中可互换使用,是指通过肽键连接的至少两个氨基酸残基的聚合物。该术语不意味着特定长度的聚合物,也不意味着暗示或区分肽是使用重组技术,化学或酶促合成产生的,还是天然存在的。该术语适用于天然存在的氨基酸聚合物以及包含至少一个修饰的氨基酸的氨基酸聚合物。在某些情况下,聚合物可被非氨基酸中断。该术语包括任何长度的氨基酸链,包括全长蛋白质,和具有或不具有二级和/或三级结构的蛋白质(例如,结构域)。该术语还包括已经被修饰的氨基酸聚合物,所述修饰例如,通过二硫键形成,糖基化,脂化,乙酰化,磷酸化,氧化和任何其他操作进行,例如与标记组分的缀合。本文所用的术语“氨基酸”通常是指天然和非天然氨基酸,包括但不限于修饰的氨基酸和氨基酸类似物。经修饰的氨基酸可包括天然氨基酸和非天然氨基酸,其已经化学修饰以包括不天然存在于氨基酸上的基团或化学部分。氨基酸类似物可以指氨基酸衍生物。术语“氨基酸”包括D-氨基酸和L-氨基酸。
当在本文中针对多肽使用时,术语“衍生物”,“变体”和“片段”是指与野生型多肽相关的多肽,例如在氨基酸序列,结构(例如,二级和/或三级),活性(例如,酶活性)和/或功能上相关。与野生型多肽相比,多肽的衍生物,变体和片段可包含一个或多个氨基酸变异(例如,突变,插入和缺失),截短,修饰或其组合。
如本文所用,“融合”可以指包含一个或多个非天然序列(例如,部分)的蛋白质和/或核酸。融合物可包含一种或多种相同的非天然序列。融合物可包含一种或多种不同的非天然序列。融合物可以是嵌合体。融合物可包含核酸亲和标签。融合物可以包括条形码。融合物可包含肽亲和标签。融合物可以提供定点多肽的亚细胞定位(例如,用于靶向细胞核的核定位信号(NLS),用于靶向线粒体的线粒体定位信号,用于靶向叶绿体的叶绿体定位信号,内质网(ER)保留信号等。融合物可以提供可以用于跟踪或纯化的非天然序列(例如,亲和标签)。融合物可以是小分子,例如生物素或染料,例如Alexa氟染料,Cyanine3染料,Cyanine5染料。
本文所用的短语“人工TCR”,可以理解为“外源性T细胞受体(TCR)复合物”,是指TCR复合物,其中TCR的一条或多条链被引入免疫细胞的基因组中,可能会也可能不会内源性地表达TCR。在一些情况下,外源TCR复合物可以指这样的TCR复合物,其中内源TCR复合物的一条或多条链具有一个或多个突变序列,例如在核酸或氨基酸水平。外源性TCR在免疫细胞上的表达可赋予表位或抗原(例如,优先存在于癌细胞或其他致病细胞或颗粒表面上的表位或抗原)的结合特异性。外源TCR复合物可包含引入基因组的TCR-α,TCR-β链,CD3-γ链,CD3-δ链,CD3-ζ链或其任何组合。在一些情况下,引入基因组的链可以取代内源性链。
术语“受试者”,“个体”和“患者”在本文中可互换使用,指脊椎动物,优选哺乳动物,例如人。哺乳动物包括但不限于鼠类,猿猴,人类,农场动物,运动动物和宠物。还包括体内获得的或体外培养的生物实体的组织,细胞及其后代。
如本文所用,术语“治疗”是指用于获得有益或所需结果的方法,包括但不限于治疗益处和/或预防益处。例如,治疗可包括施用本文公开的助推佐剂和免疫细胞。治疗益处是指治疗中的一种或多种疾病,病症或症状的任何与治疗相关的改善或作用。就预防益处,组合物可以施用于具有形成特定疾病、病症或症状的风险的受试者,或施用于报告有疾病的一种或多种生理症状的受试者,即使该疾病、病症或症状可能还没有表现出来。
术语“有效量”或“治疗有效量”是指组合物的量,例如包含本公开内容的助推佐剂和/或免疫细胞如淋巴细胞(例如,T淋巴细胞和/或NK细胞)的组合物,在给予有需要的受试者时足以产生所需的活性。在本公开内容的上下文中,术语“治疗有效”是指组合物的量足以延迟表现,阻止进展,减轻或缓解通过本发明方法治疗的病症的至少一种症状。
如本文所用,术语“遗传谱”是指关于特定基因的信息,包括个体或某种类型组织中的变异和基因表达。遗传谱可用于新抗原选择。如本文所用,术语“体细胞突变谱”是指关于与体细胞突变相关的特定基因的信息,包括但不限于由体细胞突变产生的特定基因。体细胞突变谱可用于新抗原选择。
本发明所用的术语“助推佐剂”或“佐剂”指能够辅助免疫细胞治疗的作用物,其特征在于带有助推抗原(Booster Antigen,BA),所述助推抗原是一种特定抗原,可在体内被某种特定的治疗性免疫细胞所特异性地识别,所述佐剂可借助所述助推抗原激活并助推该免疫细胞在体内进行数量上的扩增。
在一些情况下,特定的治疗性免疫细胞识别助推抗原的方式可以是使人工修饰的嵌合抗原受体(CAR)表达于治疗性免疫细胞,并且借助所述CAR特异性识别助推抗原。所述CAR是可靶向助推抗原的嵌合抗原受体(chimeric antigen receptor targeting a Booster Antigen,以下或简称“anti-Booster Antigen-CAR”或“aBA-CAR”),其结构包含可识别助推抗原的抗体的抗原结合结构域,如可变区。
在一些实施方案中,助推抗原可以是任何人类细胞广泛表达的膜蛋白的突变型,也可以是肿瘤细胞所表达的膜蛋白的突变型,这些膜蛋白包括包含I类RTK(例如,包括EGFR的表皮生长因子(EGF)受体家族;包括ErbB-2,ErbB-3和ErbB-4的ErbB家族),II类RTK(例如,胰岛素受体家族包括INSR,IGF-1R和IRR),III类RTK(例如,血小板衍生生长因子(PDGF)受体家族,包括PDGFR-α,PDGFR-β,CSF-1R,KIT/SCFR和FLK2/FLT3),IV类RTK(例如,成纤维细胞生长因子(FGF)受体家族,包括FGFR-1,FGFR-2, FGFR-3和FGFR-4),V类RTK(例如,血管内皮生长因子(VEGF)受体家族,包括VEGFR1,VEGFR2和VEGFR3),VI类RTK(例如肝细胞生长因子(HGF)受体家族,包括肝细胞生长因子受体(HGFR/MET)和RON),a VII类RTK(例如,原肌球蛋白受体激酶(Trk)受体家族,包括TRKA,TRKB和TRKC),VIII类RTK(例如,ephrin(Eph)受体家族,包括EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB3,EPHB4,EPHB5和EPHB6),IX类RTK(例如,AXL受体家族如AXL,MER和TRYO3),X类RTK(例如,LTK受体家族如LTK和ALK),XI类RTK(例如,TIE受体家族如TIE和TEK),XII类RTK(例如ROR受体家族ROR1和ROR2),XIII类RTK(例如,盘状结构域受体(DDR)家族如DDR1和DDR2),XIV类RTK(例如RET受体家族如RET),XV类RTK(例如KLG受体家族,包括PTK7),XVI类RTK(例如,RYK受体家族包括Ryk),XVII类RTK(例如,MuSK受体家族如MuSK),CD47,CD70,NKG2D,或其任何衍生物,变体或片段。
在一些实施方案中,助推抗原可包含催化受体(例如受体酪氨酸激酶(RTK))或其任何衍生物,变体或片段的至少一个细胞外区域(例如,配体结合结构域),或这些片段的突变型。在一些实施方案中,助推抗原包含I类RTK(例如,包括EGFR的表皮生长因子(EGF)受体家族;包括ErbB-2,ErbB-3和ErbB-4的ErbB家族),II类RTK(例如,胰岛素受体家族包括INSR,IGF-1R和IRR),III类RTK(例如,血小板衍生生长因子(PDGF)受体家族,包括PDGFR-α,PDGFR-β,CSF-1R,KIT/SCFR和FLK2/FLT3),IV类RTK(例如,成纤维细胞生长因子(FGF)受体家族,包括FGFR-1,FGFR-2,FGFR-3和FGFR-4),V类RTK(例如,血管内皮生长因子(VEGF)受体家族,包括VEGFR1,VEGFR2和VEGFR3),VI类RTK(例如肝细胞生长因子(HGF)受体家族,包括肝细胞生长因子受体(HGFR/MET)和RON),a VII类RTK(例如,原肌球蛋白受体激酶(Trk)受体家族,包括TRKA,TRKB和TRKC),VIII类RTK(例如,ephrin(Eph)受体家族,包括EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB3,EPHB4,EPHB5和EPHB6),IX类RTK(例如,AXL受体家族如AXL,MER和TRYO3),X类RTK(例如,LTK受体家族如LTK和ALK),XI类RTK(例如,TIE受体家族如TIE和TEK),XII类RTK(例如ROR受体家族ROR1和ROR2),XIII类RTK(例如,盘状结构域受体(DDR)家族如DDR1和DDR2),XIV类RTK(例如RET受体家族如RET),XV类RTK(例如KLG受体家族,包括PTK7),XVI类RTK(例如,RYK受体家族包括Ryk),XVII类RTK(例如,MuSK受体家族如MuSK),CD47,CD70,NKG2D,或其任何衍生物,变体或片段。
助推抗原可以包含RTK或其任何衍生物,变体或片段的突变型。RTK配体的非限制性实例包括生长因子,细胞因子和激素。生长因子包括,例如,表皮生长因子家族的成员(例如,表皮生长因子或EGF,结合肝素的EGF样生长因子或HB-EGF,转化生长因子-α或TGF-α,双调蛋白或AR,表皮调节素或EPR,epigen,betacellulin或BTC,神经调节蛋白-1或NRG1,神经调节蛋白-2或NRG2,神经调节蛋白-3或NRG3,神经调节蛋白-4或NRG4),成纤维细胞生长因子家族(如FGF1,FGF2,FGF3,FGF4,FGF5,FGF6,FGF7,FGF8,FGF9,FGF10,FGF11,FGF12,FGF13,FGF14,FGF15/19,FGF16,FGF17,FGF18,FGF20,FGF21和FGF23),血管内皮生长因子家族(如VEGF)-A,VEGF-B,VEGF-C,VEGF-D和PIGF)和血小板衍生的生长因子家族(例如,PDGFA,PDGFB,PDGFC和PDGFD)。激素包括,例如,胰岛素/IGF/松弛素家族的成员(例如,胰岛素,胰岛素样生长因子,松弛素家族肽,包括松弛素1,松弛素2,松弛素3,莱迪希细胞特异性胰岛素样肽(基因INSL3),早期胎盘胰岛素样肽(ELIP)(基因INSL4),胰岛素样肽5(基因INSL5)和胰岛素样肽6。
在一些实施方案中,助推抗原至少包含催化受体的细胞外区域(例如,配体结合结构域),例如受体苏氨酸/丝氨酸激酶(RTSK),或其任何衍生物,变体或片段,或包含以这些片段作为抗原的抗体可变区的片段。助推抗原可包含I型RTSK,II型RTSK或其任何衍生物,变体或片段。助推抗原可包含I型受体,或其任何衍生物,变体或片段,选自:ALK1(ACVRL1),ALK2(ACVR1A),ALK3(BMPR1A),ALK4(ACVR1B),ALK5(TGFβR1),ALK6(BMPR1B)和ALK7(ACVR1C)。助推抗原可包含II型受体,或其选自下组的任何衍生物,变体或片段:TGFβR2,BMPR2,ACVR2A,ACVR2B和AMHR2(AMHR)。在一些实施方案中,助推抗原包含TGF-β。
助推抗原包含RTSK或其任何衍生物或其突变型。
在一些情况下,助推抗原是B细胞表面蛋白或其片段。B细胞表面蛋白可以是可以在B细胞表面上发现的任何蛋白质。非限制性实例包括CD1d,CD5,CD10,CD11a,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD27,CD28,CD29,CD34,CD37,CD38,CD40,CD44,CD45,CD49b,CD69,CD72。CD74,CD80,CD83,CD84,CD86,CD93,CD95,CD117,CD127,CD138,CD147,CD148,CD185,CD270,CD284和CD360。在一些实施方案中,CAR的抗原相互作用结构域能够结合非B细胞上的表面蛋白,只要与表面蛋白的结合不显著损害宿主的一般健康状态或免疫系统。在一些实施方案中,表面蛋白质是免疫细胞上的表面蛋白质。在一些实施方案中,表面蛋白质是免疫细胞以外的细胞上的表面蛋白质。在一些实施方案中,所述表面蛋白可以选自CD31,CD32(A,B), CD33,CD34,CD35,CD36,CD37,CD38,CD39,CD40,CD41,CD42(a,b,c,d),CD43,CD44,CD45,CD46,CD47,CD48,CD49(a,b,c,d,e,f),CD50,CD51,CD52,CD53,CD54,CD55,CD56,CD57,CD58,CD59,CD61,CD62(E,L,P),CD63,CD64(A,B,C),CD66(a,b,c,d,e,f),CD68,CD69,CD70,CD71,CD72,CD73,CD74,CD78,CD79(a,b),CD80,CD81,CD82,CD83,CD84,CD85(a,d,e,h,j,k),CD86,CD87,CD88,CD89,CD90,CD91,CD92,CD93,CD94,CD95,CD96,CD97,CD98,CD99,CD100,CD1(ac),1A,1D,1E,CD2,CD3(γ,δ,ε),CD4,CD5,CD6,CD7,CD8,a,CD9,CD10,CD11(a,b,c,d),CD13,CD14,CD15,CD16,A,B,CD18,CD19,CD20,CD21,CD22,CD23,CD24,CD25,CD26,CD27,CD28,CD29,CD30,CD101,CD102,CD103,CD104,CD105,CD106,CD107(a,b),CD108,CD109,CD110,CD111,CD1 12,CD113,CD114,CD115,CD116,CD117,CD118,CD119,CD120(a,b),CD121(a,b),CD122,CD123,CD124,CD125,CD126,CD127,CD129,CD130,CD131,CD132,CD133,CD134,CD135,CD136,CD137,CD138,CD140b,CD141,CD142,CD143,CD144,CD146,CD147,CD148,CD150,CD191,CD192,CD193,CD194,CD195,CD196,CD197,CDw198,CDw199,CD200,CD201,CD202b,CD204,CD205,CD206,CD207,CD208,CD209,CDw210(a,b),CD212,CD213a(1,2),CD217,CD218,(a,b),CD220,CD221,CD222,CD223,CD224,CD225,CD226,CD227,CD228,CD229,CD230,CD233,CD234,CD235(a,b),CD236,CD238,CD239,CD240CE,CD240D,CD241,CD243,CD244,CD246,CD247,CD248,CD249,CD252,CD253,CD254,CD256,CD257,CD258,CD261,CD262,CD263,CD264,CD265,CD266,CD267,CD268,CD269,CD271,CD272,CD273,CD274,CD275,CD276,CD278,CD279,CD280,CD281,CD282,CD283,CD284,CD286,CD288,CD289,CD290,CD292,CDw293,CD294,CD295,CD297,CD298,CD299,CD300A,CD301,CD302,CD303,CD304,CD305,CD306,CD307,CD309,CD312,CD314,CD315,CD316,CD317,CD318,CD320,CD321,CD322,CD324,CD325,CD326,CD328,CD329,CD331,CD332,CD333,CD334,CD335,CD336,CD337,CD338,CD339,CD340,CD344,CD349,CD350,CD151,CD152,CD153,CD154,CD155,CD156(a,b,c),CD157,CD158(a,d,e,i,k),CD159(a,c),CD160,CD161,CD162,CD163,CD164,CD166,CD167(a,b),CD168,CD169,CD170,CD171,CD172(a,b,g),CD174,CD177,CD178,CD179(a,b),CD180,CD181,CD182,CD183,CD184, CD185和CD186,条件是与表面蛋白的结合不会显著损害宿主的一般健康状态或免疫系统。
在一些情况下,助推抗原是NK细胞,粒细胞,红细胞,血小板表面蛋白的全部或部分片段。
在一些情况下,助推抗原是病原体如病毒、细菌、真菌的表面标志物或跨膜蛋白或其片段,所述病原体包括HPV病毒,EB病毒,幽门螺旋杆菌(HP),乙肝病毒(HBV),艾滋病毒(HIV)。
在一些情况下,助推抗原是任意一种人类细胞内蛋白或其片段。
在一些情况下,助推抗原是任意一种人类细胞外分泌蛋白或其片段。
在一些实施例中,助推抗原是一种人类天然蛋白的全部或部分片段的野生型或突变型,或多种人类天然蛋白的全部或部分片段的野生型或突变型的组合物。
在一些实施例中,助推抗原是CD19或EGFRviii(包括完整的EGFRviii,或EGFRviiit,即截短的EGFRviii),或是包含CD19和/或CD86和/或CD137L和/或mbIL15(膜结合的白介素15,membrane-bound IL15)和/或IL15Ra(IL15受体的α亚基)的组合物,或是包含EGFRviii和/或CD86和/或CD137L和/或mbIL15和/或IL15Ra的组合物。
在一些情况下,助推佐剂可以是包含助推抗原的蛋白,或化合物、复合物,或细胞(以下或称“助推性细胞”),或人工纳米材料。
在一些实施方案中,助推抗原可以偶联(例如,通过共价和/或非共价键)至颗粒(例如,纳米颗粒)表面。颗粒可以是包含有机和/或无机材料的任何颗粒材料。颗粒可具有各种形状和尺寸。颗粒在至少一个维度上可以是约1纳米(nm)至约50微米(μm)。颗粒在至少一个维度上可以是至少约1nm,5nm,10nm,50nm,100nm,500nm,1μm,5μm,10μm,50μm或更多。颗粒在至少一个维度上可以是至多约50μm,10μm,5μm,1μm,500nm,100nm,50nm,10nm,5nm,1nm或更小。颗粒可以是纳米颗粒,微颗粒,纳米球,微球,纳米棒,微米棒,纳米纤维,纳米带等。颗粒的实例包括金属纳米颗粒(例如,金纳米颗粒,银纳米颗粒和铁纳米颗粒),金属间纳米半导体纳米颗粒,核-壳纳米颗粒,具有聚合物壳的无机核的颗粒,具有聚合物壳的有机核的颗粒,以及它们的混合物。或者,颗粒可以是有机纳米颗粒,例如交联聚合物,水凝胶聚合物,可生物降解的聚合物,聚丙交酯(PLA),聚乙交酯(PGA),聚己内酯(PCL),共聚物,多糖,淀粉,纤维素,壳聚糖,聚羟基链烷酸酯(PHA),PHB,PHV,脂质,肽,肽两亲物,多肽(例如蛋白质)或其组合。在表面上呈递B细胞表面蛋白的颗粒可以在体外引入包含结合B细胞表面蛋白的CAR的免疫细胞。作为另外一种选择或除此之外,呈递B细胞表面蛋白的颗粒可以与包含CAR的免疫细胞一 起体内引入(例如局部或全身注射)。这些颗粒可用于在体外或体内扩增包含CAR的免疫细胞群。
在一些情况下,助推佐剂是助推性细胞,且所述助推性细胞是源自患者自体或异体外周血单个核细胞(PBMC)或B细胞、T细胞、NK细胞等任意某一类细胞或多类细胞的混合物,该细胞是天然未经修饰的细胞,或是经过修饰的细胞,或是经过永生化改造的B细胞或NK细胞(如NK92)或K562细胞。
在一些情况下,助推佐剂是助推性细胞(如T细胞),且助推抗原跨膜表达在所述助推性细胞上,所述助推抗原是由胞外结合域和跨膜区域组成的融合蛋白,其中所述胞外结合域是特定治疗性免疫细胞可识别的结构(如EGFRviii或CD19),所述跨膜区域是所述助推性细胞的天然表达的蛋白的部分或全部结构(如CD3)。
aBA-CAR的“抗原结合结构域”可包含能够结合助推抗原的任何蛋白质或分子。抗原结合结构域的非限制性实例包括但不限于单克隆抗体,多克隆抗体,重组抗体,人抗体,人源化抗体,鼠抗体或其功能衍生物,变体或片段,包括但不限于Fab,Fab',F(ab')2,Fv,单链Fv(scFv),微抗体,双抗体和单结构域抗体如重链可变结构域(VH),骆驼科动物衍生的纳米抗体的轻链可变结构域(VL)和可变结构域(VHH)。在一些实施方案中,抗原结合结构域包含Fab,Fab',F(ab')2,Fv和scFv中的至少一种。在一些实施方案中,抗原结合结构域包含抗体模拟物。抗体模拟物是指能够以与抗体相当的亲和力结合靶分子的分子,包括单链结合分子,基于细胞色素b562的结合分子,纤连蛋白或纤连蛋白样蛋白支架(例如,adnectin),脂质运载蛋白支架,杯芳烃支架,A域和其他支架。在一些实施方案中,抗原结合结构域包含跨膜受体或其任何衍生物,变体或片段。例如,抗原结合结构域可以包含至少跨膜受体的配体结合结构域。
在一些实施方案中,aBA-CAR的“抗原结合结构域”可包含scFV。scFv可以衍生自已知可变区序列的抗体。在一些实施方案中,scFv可衍生自获自可获得的小鼠杂交瘤的抗体序列。scFv可以从肿瘤细胞或原代细胞的全体外显子测序中获得。在一些实施方案中,可以修饰scFv。例如,可以以各种方式修饰scFv。在一些情况下,可以突变scFv,使得scFv可以对其靶标具有更高的亲和力。在一些情况下,scFv对其靶标的亲和力可以针对在正常组织上以低水平表达的靶标进行优化。可以进行该优化以最小化潜在的毒性,例如高细胞因子血症。在其他情况下,克隆对靶膜结合形式具有更高亲和力的scFv可优于其可溶形式对应物。如果某些靶标也可以以不同水平的可溶形式检测,并且它们的靶向可以引起非预期的毒性,例如高细胞因子血症,则可以进行该修饰。
可以通过跨膜结构域将本系统的aBA-CAR的抗原结合结构域与细胞内信号传导结构域连接。跨膜结构域可以是跨膜区段。受试者CAR的跨膜结构域可以将CAR锚定到细胞的质膜,例如免疫细胞。在一些实施方案中,跨膜区段包含多肽。连接CAR的抗原结合结构域和细胞内信号传导结构域的跨膜多肽可具有任何合适的多肽序列。在一些情况下,跨膜多肽包含内源或野生型跨膜蛋白的跨膜部分的多肽序列。在一些实施方案中,跨膜多肽包含具有至少1个(例如,至少2,3,4,5,6,7,8,9,10或更多个)氨基酸取代,缺失和多肽的多肽序列。插入与内源或野生型跨膜蛋白的跨膜部分相比。在一些实施方案中,跨膜多肽包含非天然多肽序列,例如多肽接头的序列。多肽接头可以是柔性的或刚性的。多肽接头可以是结构化的或非结构化的。在一些实施方案中,跨膜多肽通过抗原结合结构域将信号从细胞的细胞外区域传递至细胞内区域。CD28的天然跨膜部分可用于aBA-CAR。在其他情况下,CD8α的天然跨膜部分也可用于aBA-CAR。
本公开内容的CAR,包括aBA-CAR,可包含参与免疫细胞信号传导的信号传导结构域或其任何衍生物,变体或片段。CAR的细胞内信号传导结构域可以诱导包含CAR的免疫细胞的活性。细胞内信号传导结构域可以转导效应子功能信号并指导细胞执行特化功能。信号传导结构域可包含其他分子的信号传导结构域。在一些情况下,将信号传导结构域的截短部分用于CAR。
在一些实施方案中,细胞内信号传导结构域包含参与免疫细胞信号传导的多个信号传导结构域,或其任何衍生物,变体或片段。例如,细胞内信号传导结构域可包含至少2个免疫细胞信号传导结构域,例如至少2,3,4,5,7,8,9或10个免疫细胞信号传导结构域。免疫细胞信号传导结构域可以以刺激方式或抑制方式参与调节TCR复合物的初级激活。细胞内信号传导结构域可以是T细胞受体(TCR)复合物的信号传导结构域。本发明的CAR的细胞内信号传导结构域可包含Fcγ受体(FcγR),Fcε受体(FcεR),Fcα受体(FcαR),新生儿Fc受体(FcRn),CD3,CD3ζ,CD3γ,CD3δ,CD3ε,CD4,CD5,CD8,CD21,CD22,CD28,CD32,CD40L(CD154),CD45,CD66d,CD79a,CD79b,CD80,CD86,CD278(也称为ICOS),CD247ζ,CD247η,DAP10,DAP12,FYN,LAT,Lck,MAPK,MHC复合物,NFAT,NF-κB,PLC-γ,iC3b,C3dg,C3d和Zap70的信号传导结构域。在一些实施方案中,信号传导结构域包括基于免疫受体酪氨酸的活化基序或ITAM。包含ITAM的信号传导结构域可包含两个重复的氨基酸序列YxxL/I,其间隔6-8个氨基酸,其中每个x独立地为任何氨基酸,产生保守基序YxxL/Ix
(6-8)YxxL/I。当抗原结合结构域与表位结合时,可以修饰包含ITAM的信号传导结构域,例如通过磷酸化。磷酸化的ITAM可以作为其他蛋白质的停靠位点,例如参与各种信号传导途径的蛋白质。在一些实施方案中,主要信号 传导结构域包含修饰的ITAM结构域,例如突变的,截短的和/或优化的ITAM结构域,其与天然ITAM结构域相比具有改变的(例如,增加的或减少的)活性。
在一些实施方案中,CAR(包括aBA-CAR)的细胞内信号传导结构域包含FcγR信号传导结构域(例如,ITAM)。FcγR信号传导结构域可选自FcγRI(CD64),FcγRIIA(CD32),FcγRIIB(CD32),FcγRIIIA(CD16a)和FcγRIIIB(CD16b)。在一些实施方案中,细胞内信号传导结构域包含FcεR信号传导结构域(例如,ITAM)。FcεR信号传导结构域可选自FcεRI和FcεRII(CD23)。在一些实施方案中,细胞内信号传导结构域包含FcαR信号传导结构域(例如,ITAM)。FcαR信号传导结构域可选自FcαRI(CD89)和Fcα/μR。在一些实施方案中,细胞内信号传导结构域包含CD3ζ信号传导结构域。在一些实施方案中,主要信号传导结构域包含CD3ζ的ITAM。
在一些实施方案中,CAR(包括aBA-CAR)的细胞内信号传导结构域包含基于免疫受体酪氨酸的抑制基序或ITIM。包含ITIM的信号传导结构域可包含保守的氨基酸序列(S/I/V/LxYxxI/V/L),其存在于免疫系统的一些抑制性受体的细胞质尾部。包含ITIM的主要信号传导结构域可以通过酶(例如Src激酶家族成员(例如Lck))进行修饰,例如磷酸化。磷酸化后,其他蛋白质,包括酶,可以募集到ITIM。这些其他蛋白质包括但不限于酶,例如磷酸酪氨酸磷酸酶SHP-1和SHP-2,称为SHIP的肌醇磷酸酶,和具有一个或多个SH2结构域的蛋白质(例如ZAP70)。细胞内信号传导结构域可包含BTLA,CD5,CD31,CD66a,CD72,CMRF35H,DCIR,EPO-R,FcγRIIB(CD32),Fc受体样蛋白2(FCRL2),Fc受体样蛋白3(FCRL3),Fc受体样蛋白4(FCRL4),Fc受体样蛋白5(FCRL5),Fc受体样蛋白6(FCRL6),蛋白G6b(G6B),白细胞介素4受体(IL4R),免疫球蛋白超家族受体易位相关1(IRTA1),免疫球蛋白超家族受体易位相关2(IRTA2),杀伤细胞免疫球蛋白样受体2DL1(KIR2DL1),杀伤细胞免疫球蛋白样受体2DL2(KIR2DL2),杀伤细胞免疫球蛋白样受体2DL3(KIR2DL3),杀伤细胞免疫球蛋白样受体2DL4(KIR2DL4),杀伤细胞免疫球蛋白样受体2DL5(KIR2DL5),杀伤细胞免疫球蛋白样受体3DL1(KIR3DL1),杀伤细胞免疫球蛋白样受体3DL2(KIR3DL2),白细胞免疫球蛋白样受体亚家族B成员1(LIR1),白细胞免疫球蛋白样受体亚家族B成员2(LIR2),白细胞免疫球蛋白样受体亚家族B成员3(LIR3),白细胞免疫球蛋白样受体亚家族B成员5(LIR5),白细胞免疫球蛋白样受体亚家族B成员8(LIR8),白细胞相关免疫球蛋白样受体1(LAIR-1),肥大细胞功能相关抗原(MAFA),NKG2A,天然细胞毒性触发受体2(NKp44),NTB-A,程序性细胞死亡蛋白1(PD-1),PILR,SIGLECL1,唾液酸结合Ig如凝集素2(SIGLEC2或CD22),唾液酸结合Ig如凝集素3(SIGLEC3或CD33),唾液酸结合Ig如凝集素5(SIGLEC5或CD170),唾液酸结合Ig如 凝集素6(SIGLEC6),唾液酸结合Ig如凝集素7(SIGLEC7),唾液酸结合Ig如凝集素10(SIGLEC10),唾液酸结合Ig如凝集素11(SIGLEC11),唾液酸结合Ig如凝集素4(SIGLEC4),唾液酸酸结合Ig如凝集素8(SIGLEC8),唾液酸结合Ig如凝集素9(SIGL EC9),血小板和内皮细胞粘附分子1(PECAM-1),信号调节蛋白(SIRP2)和信号阈值调节跨膜衔接子1(SIT)的信号传导结构域(例如,ITIM)。。在一些实施方案中,细胞内信号传导结构域包含修饰的ITIM结构域,例如突变的,截短的和/或优化的ITIM结构域,其与天然ITIM结构域相比具有改变的(例如,增加的或减少的)活性。
在一些实施方案中,CAR(包括aBA-CAR)的细胞内信号传导结构域包含至少2个ITAM结构域(例如,至少3个,4个,5个,6个,7个,8个,9个或10个ITAM结构域)。在一些实施方案中,细胞内信号传导结构域包含至少2个ITIM结构域(例如,至少3个,4个,5个,6个,7个,8个,9个或10个ITIM结构域)(例如,至少2个主要信号传导结构域)。在一些实施方案中,细胞内信号传导结构域包括ITAM和ITIM结构域。
在一些情况下,CAR(包括aBA-CAR)的细胞内信号传导结构域可包括共刺激结构域。在一些实施方案中,共刺激结构域,例如来自共刺激分子,可以为免疫细胞信号传导提供共刺激信号,例如来自ITAM和/或ITIM结构域的信号传导,例如,用于激活和/或失活免疫细胞活动。在一些实施方案中,共刺激结构域可用于调节免疫细胞中的增殖和/或存活信号。在一些实施方案中,共刺激信号传导结构域包含MHC I类蛋白,MHC II类蛋白,TNF受体蛋白,免疫球蛋白样蛋白,细胞因子受体,整联蛋白,信号传导淋巴细胞活化分子(SLAM蛋白),激活NK细胞受体,BTLA或Toll配体受体的信号传导结构域。在一些实施方案中,共刺激结构域包含选自下组的分子的信号传导结构域:2B4/CD244/SLAMF4,4-1BB/TNFSF9/CD137,B7-1/CD80,B7-2/CD86,B7-H1/PD-L1,B7-H2,B7-H3,B7-H4,B7-H6,B7-H7,BAFF R/TNFRSF13C,BAFF/BLyS/TNFSF13B,BLAME/SLAMF8,BTLA/CD272,CD100(SEMA4D),CD103,CD11a,CD11b,CD11c,CD11d,CD150,CD160(BY55),CD18,CD19,CD2,CD200,CD229/SLAMF3,CD27配体/TNFSF7,CD27/TNFRSF7,CD28,CD29,CD2F-10/SLAMF9,CD30配体/TNFSF8,CD30/TNFRSF8,CD300a/LMIR1,CD4,CD40配体/TNFSF5,CD40/TNFRSF5,CD48/SLAMF2,CD49A,CD49D,CD49f,CD5,CD53,CD58/LFA-3,CD69,CD7,CD8α,CD8β,CD82/Kai-1,CD84/SLAMF5,CD90/Thy1,CD96,CDS,CEACAM1,CRACC/SLAMF7,CRTAM,CTLA-4,DAP12,Dectin-1/CLEC7A,DNAM1(CD226),DPPIV/CD26,DR3/TNFRSF25,EPHB6,GADS,Gi24/VISTA/B7-H5,GITR配体/TNFSF18,GITR/TNFRSF18,HLA I类,HLA-DR,HVEM/TNFRSF14,IA4,ICAM-1,ICOS/CD278, Ikaros基因,IL2Rβ,IL2Rγ,IL7Rα,整合素α4/CD49d,整合素α4β1,整合素α4β7/LPAM-1,IPO-3,ITGA4,ITGA6,ITGAD,ITGAE,ITGAL,ITGAM,ITGAX,ITGB1,ITGB2,ITGB7,KIRDS2,LAG-3,LAT,LIGHT/TNFSF14,LTBR,Ly108,LY9(CD229),淋巴细胞功能相关抗原-1(LFA-1),淋巴毒素-α/TNF-β,NKG2C,NKG2D,NKp30,NKp44,NKp46,NKp80(KLRF1),NTB-A/SLAMF6,OX40配体/TNFSF4,OX40/TNFRSF4,PAG/Cbp,PD-1,PDCD6,PD-L2/B7-DC,PSGL1,RELT/TNFRSF19L,SELPLG(CD162),SLAM(SLAMF1),SLAM/CD150,SLAMF4(CD244),SLAMF6(NTB-A),SLAMF7,SLP-76,TACI/TNFRSF13B,TCL1A,TCL1B,TIM-1/KIM-1/HAVCR,TIM-4,TL1A/TNFSF15,TNF RII/TNFRSF1B,TNF-α,TRANCE/RANKL,TSLP,TSLP R,VLA1和VLA-6。在一些实施方案中,细胞内信号传导结构域包含多个共刺激结构域,例如至少两个,例如至少3,4或5个共刺激结构域。共刺激信号传导区域可以提供与初级效应子激活信号协同的信号,并且可以完成激活T细胞的要求。在一些实施方案中,向CAR添加共刺激结构域可以增强本文提供的免疫细胞的功效和持久性。
与缺乏CAR特别是aBA-CAR的免疫细胞相比,CAR特别是aBA-CAR与助推抗原的结合可以增强免疫细胞增殖。免疫细胞的增殖可以指免疫细胞的扩增。免疫细胞的增殖可以指免疫细胞的表型变化。包含本文的CAR特别是aBA-CAR的免疫细胞的增殖可以大于缺乏所述CAR的免疫细胞的增殖。包含CAR的免疫细胞的增殖相比于缺乏CAR的细胞可为约5倍至约10倍,约10倍至约20倍,约20倍至约30倍,约30倍至约40倍,约40倍至约50倍,约50倍至约60倍,约60倍至约70倍,约70倍至约80倍,约80倍至约90倍,约90倍至约100倍,约100倍至约200倍,约为200倍至约300倍,约300倍至约400倍,约400倍至约500倍,约500倍至约600倍,比相当免疫的增殖大约600倍至约700倍。包含CAR的免疫细胞的增殖可为缺乏CAR的细胞的约5倍至约10倍,约10倍至约20倍,约20倍至约30倍,约30倍至约40倍,约40倍至约50倍,约50倍至约60倍,约60倍至约70倍,约70倍至约80倍,约80倍至约90倍,约90倍至约100倍,约100倍至约200倍,约为200倍至约300倍,约300倍至约400倍,约400倍至约500倍,约500倍至约600倍,比相当免疫的增殖大约600倍至约700倍,并且其中在使助推抗原与所述免疫细胞接触后至少约12,24,36,48,60,72,84或96小时确定增殖。可以在体外或体内确定增殖的增强。在一些实施方案中,增殖可包括定量免疫细胞的数量。定量免疫细胞可包括流式细胞术,台盼蓝排除法和/或血细胞计数法。也可以通过免疫细胞的表型分析来确定增殖。
在一些情况下,CAR结构可以包括表达调控元件,其可以是CAR或CAR-T细胞表达调控和/或令CAR-T或CAR-NK细胞自杀或凋亡的开关元件,例如TET-ON。
在一些实施例中,治疗性免疫细胞是T细胞,或NK细胞。
在一些实施例中,治疗性免疫细胞是人工修饰的T细胞,或NK细胞,如CAR-T、CAR-NK、TCR-T、TCR-NK细胞。
在一个方面,本公开的治疗性免疫细胞是肿瘤浸润淋巴细胞(TIL),其特异性结合肿瘤相关抗原,包括但不限于新抗原(neoantigen)。修饰的TIL可包含嵌合刺激分子。嵌合刺激分子可包含结合新抗原的多肽细胞外结构域(PED)。PED可以与介导免疫细胞活化信号的共刺激分子的细胞内结构域(ICD)融合。嵌合刺激分子与新抗原的结合可以在修饰的TIL中产生免疫细胞活化信号。在一些实施方案中,PED可以是未修饰的TIL的表面蛋白的细胞外结构域。在一些实施方案中,PED的实例包括抗体,以及其衍生物,变体和片段。
在一个方面,本公开内容提供了经修饰的T细胞,该T细胞具有双重识别特性,所述双重识别性之一方面是指对靶细胞的识别性,即所述T细胞一方面可识别并杀伤靶细胞,所述靶细胞是对人体有害的细胞如肿瘤细胞,或病毒、病菌等非肿瘤细胞;另一方面是指对助推抗原的识别性,即所述免疫细胞可独立识别助推抗原或带有助推抗原的佐剂而被激活进而扩增其数量。
在一个方面,本公开内容提供了经aBA-CAR修饰的T细胞,该T细胞具有双重识别特性,所述双重识别性之一方面是指对靶细胞的识别性,即所述T细胞一方面可识别并杀伤靶细胞,所述靶细胞是对人体有害的细胞如肿瘤细胞,或病毒、病菌等非肿瘤细胞;另一方面是指对助推抗原的识别性,即所述免疫细胞可借助aBA-CAR独立识别助推抗原或带有助推抗原的佐剂而被激活进而扩增其数量。
在一个方面,本公开内容提供了经aBA-CAR并且经TCR或CAR(不同于aBA-CAR的另一种CAR)修饰的T细胞,该T细胞具有双重识别特性,所述双重识别性之一方面是指对靶细胞的识别性,即所述T细胞带有人工(或称外源性)TCR或CAR(非aBA-CAR的另一种CAR),可借助所述人工TCR或CAR识别并杀伤靶细胞,所述靶细胞是对人体有害的细胞如肿瘤细胞,或病毒、病菌等非肿瘤细胞;另一方面是指对助推抗原的识别性,即所述免疫细胞可借助aBA-CAR独立识别助推抗原或带有助推抗原的佐剂而被激活进而扩增其数量。
在一些实施例中,所述免疫细胞识别靶细胞的靶点和识别助推抗原的靶点是不同的,或是相同的。
在一个方面,本公开内容提供了经aBA-CAR修饰的肿瘤识别性T细胞或肿瘤抗原反应性T细胞,该T细胞具有双重识别特性,所述双重识别性之一方面是指对肿瘤细胞的识别性,即所述T细胞一方面可识别并杀伤肿瘤细胞;另一方面是指对助推抗原的识别性,即所述免疫细胞可借助aBA-CAR独立识别助推抗原或带有助推抗原的佐剂而被激活进而扩增其数量。
肿瘤识别性T细胞(或肿瘤抗原反应性T细胞)对肿瘤的识别可以是借助天然未经修饰的TCR来识别新抗原(neoantigen),或肿瘤相关抗原(TAA),或癌睾抗原,或病毒抗原(如HPV或EBV病毒感染而癌变的细胞表面的病毒抗原)等。这类肿瘤识别性T细胞可以经疫苗诱导获得,也可以是从肿瘤浸润淋巴细胞(TIL)中获得,也可以借助外周血的某些标志物(如PD1、TIM3、CD137、CD39、CD28等)的阳性或阴性筛选而得到。
肿瘤识别性T细胞对肿瘤的识别也可以是借助人工修饰的CAR或TCR,形成CAR-T或TCR-T来识别相关的肿瘤细胞。
肿瘤浸润淋巴细胞(TIL)可以是从肿瘤获得的任何细胞。例如,TIL可以是已迁移至肿瘤的细胞。TIL可以是已经渗入肿瘤的细胞。在一些实施方案中,TIL是白细胞,其已经从受试者的血流迁移到肿瘤中。TIL可以是例如T细胞,B细胞,单核细胞或自然杀伤(NK)细胞。在一些情况下,修饰的TIL包含CD8+细胞毒性T细胞(淋巴细胞),Th1和Th17CD4+T细胞,天然杀伤细胞,树突细胞或M1巨噬细胞。包含TIL的免疫细胞群可以是混合的细胞群。TIL群可包含不同表型的细胞,不同分化程度的细胞,不同谱系的细胞或其任何组合。TIL通常可以通过生物化学,使用细胞表面标志物,或通过其渗透肿瘤和影响治疗的能力在功能上来定义。TIL可以基于以下生物标志物中的一种或多种的表达进行分类:CD4,CD8,TCRαβ,CD25,CD27,CD28,CD39,CD56,CD137,CCR7,CD45Ra,CD95,PD-1和TIM-3。在一些实施方案中,修饰的TIL表达PD-1,CD39,CD137和TIM-3中的至少一种。在一些情况下,TIL在功能上可以通过其在重新引入患者时渗透实体瘤的能力来定义。在一些情况下,修饰的TIL包含“初级TIL”,指的是从患者组织样品获得的TIL。在一些情况下,修饰的TIL包含“次级TIL”,指的是已经扩增或增殖的TIL。TIL可以表现出与新抗原的特异性结合。在一些情况下,TIL的TCR复合物赋予抗原结合特异性(例如,新抗原结合)。
在一些实施方案中,免疫细胞是肿瘤浸润淋巴细胞(TIL)。TIL可以是例如T细胞,B细胞,单核细胞或自然杀伤(NK)细胞。在一些情况下,TIL包含CD8+细胞毒性T细胞(淋巴细胞),Th1和Th17CD4+T细胞,天然杀伤细胞,树突细胞或M1巨噬细胞。在一些实施方案中,TIL可以表达PD-1,CD137和TIM-3中的至少一种。在一些情况下, 修饰的TIL包含“初级TIL”,指的是从患者组织样品获得的TIL。在一些情况下,修饰的TIL包含“次级TIL”,指的是已经扩增或增殖的TIL。
在一些情况下,TIL可以离开肿瘤组织而存在于外周血中。在一些实施例中,TIL可以并非取材自肿瘤组织。在一些实施例中,TIL可以借助单采分离外周血单核细胞(PBMC)获得,或者进一步经PD1、TIM3、CD137、CD39等一种或多种标志物进行筛选富集而获得。
在一个方面,本公开提供了特异性结合新抗原的经修饰的T细胞,所述经修饰的T细胞不仅包含aBA-CAR,还包含增强受体。增强受体可包含蛋白质的细胞外结构域(ECD)。ECD可以与介导免疫细胞活化信号的共刺激分子的细胞内结构域(ICD)融合。增强受体与配体的结合可以在修饰的T细胞中产生免疫细胞活化信号,而不是免疫细胞失活信号。
修饰的T细胞可包含T细胞受体(TCR)复合物,其表现出与新抗原的特异性结合。在一些实施方案中,TCR复合物是内源性TCR复合物。在一些实施方案中,TCR是外源TCR复合物。修饰的免疫细胞的TCR复合物(例如内源或外源)可赋予免疫细胞的抗原结合特异性(例如,新抗原结合)。在一些实施方案中,本公开内容提供了修饰的T细胞,其包含特异性结合新抗原的内源性TCR复合物,所述修饰的T细胞包含嵌合刺激分子,其中所述嵌合刺激分子包含:结合的多肽细胞外结构域(PED)包括但不限于肿瘤细胞的细胞上的膜蛋白,其中所述PED与介导免疫细胞活化信号的共刺激分子的细胞内结构域(ICD)融合,其中所述嵌合刺激分子与所述嵌合刺激分子结合。所述膜蛋白在所述修饰的T细胞中产生所述免疫细胞激活信号。
修饰的免疫细胞(例如本文提供的修饰的T细胞或修饰的TIL)与新抗原的结合可以激活免疫细胞。修饰细胞的增强受体可用于提供对免疫细胞活性的进一步控制,例如但不限于免疫细胞活化和扩增。增强受体与修饰的免疫细胞(例如修饰的T细胞或修饰的TIL)中的配体的结合可以在修饰的免疫细胞中引发免疫细胞活化信号而不是免疫细胞失活信号。在修饰的免疫细胞中引发免疫细胞活化信号而不是免疫细胞失活信号可以使免疫细胞中的免疫抑制作用最小化。最小化免疫细胞中的免疫抑制作用可以增加免疫细胞在免疫应答中的有效性,例如通过增加针对靶细胞(例如肿瘤细胞)的免疫细胞细胞毒性。
增强受体可包含蛋白质的细胞外结构域(ECD),其在未修饰的免疫细胞中在与其配体结合后引发免疫细胞信号,该信号可以是失活信号,也可以是激活信号,也可以既不是激活也非失活信号。蛋白质可以是信号传导受体或其任何功能片段,衍生物或变体。在一些情况下,信号传导受体可以是膜结合受体。响应于配体结合,信号传导受体可以诱导 细胞中的一种或多种信号传导途径。在一些情况下,信号传导受体可以是非膜结合受体。增强受体可包含选自G蛋白偶联受体(GPCR)的受体的片段,例如细胞外结构域;整合素受体;钙粘蛋白受体;催化受体(例如激酶);死亡受体;检查点受体;细胞因子受体;趋化因子受体;生长因子受体;激素受体;和免疫受体。
在一些实施方案中,增强受体包含免疫检查点受体的片段,其可以参与免疫系统的调节。此类受体的非限制性实例包括但不限于程序性细胞死亡1(PD-1,或PD1),细胞毒性T淋巴细胞相关蛋白4(CTLA-4),B和T淋巴细胞衰减剂(BTLA),杀伤性免疫球蛋白类似受体(KIR),吲哚胺2,3-双加氧酶(IDO),淋巴细胞活化基因-3(LAG3),T细胞免疫球蛋白粘蛋白3(TIM-3),具有Ig和ITIM结构域的T细胞免疫受体(TIGIT),SIRPα,NKG2D。
在一些实施方案中,增强受体包含至少TCR的细胞外片段,其可参与识别靶细胞的新抗原(例如,癌细胞抗原或肿瘤抗原)。在一些实例中,增强受体可包含TCRα和/或β链的细胞外可变区。
增强受体可以包含免疫检查点受体或其任何衍生物,变体或片段。增强受体可以结合包含任何合适的免疫检查点受体配体或其任何衍生物,变体或片段的抗原。此类配体的非限制性实例包括但不限于B7-1,B7-H3,B7-H4,HVEM(疱疹病毒进入介质),AP2M1,CD80,CD86,SHP-2,PPP2R5A,MHC(例如,I类,II类),CD47,CD70,PD-L1(或PDL1)和PD-L2。增强受体与此类配体结合的区域,可以是此类配体的天然受体,也可以是此类配体的单克隆抗体。
在一些实施方案中,增强受体包含细胞因子受体的片段。细胞因子受体可以发挥多种功能,其非限制性实例包括免疫细胞调节和介导炎症。在一些实施方案中,增强受体包含细胞因子受体,例如I型细胞因子受体或II型细胞因子受体,或其任何衍生物,变体或片段。在一些实施方案中,增强受体包含白细胞介素受体(例如,IL-2R,IL-3R,IL-4R,IL-5R,IL-6R,IL-7R,IL-9R,IL-11R,IL-12R,IL-13R,IL-15R,IL-21R,IL-23R,IL-27R和IL-31R),一种集落刺激因子受体(例如,促红细胞生成素受体,CSF-1R,CSF-2R,GM-CSFR和G-CSFR),激素受体/神经肽受体(例如,生长激素受体,催乳素受体和瘦蛋白受体),或其任何衍生物,变体或片段。在一些实施方案中,增强受体包含II型细胞因子受体,或其任何衍生物,变体或片段。在一些实施方案中,增强受体包含干扰素受体(例如,IFNAR1,IFNAR2和IFNGR),白细胞介素受体(例如,IL-10R,IL-20R,IL-22R和IL-28R),组织因子受体。(也称为血小板组织因子),或其任何衍生物,变体或片段。
在一些实施方案中,增强受体的细胞外结合域可以是任何抗体或抗体的片段,该抗体所结合的抗原可以是任何人类细胞广泛表达的膜蛋白,也可以是肿瘤细胞所表达的 膜蛋白,这些膜蛋白包括包含I类RTK(例如,包括EGFR的表皮生长因子(EGF)受体家族;包括ErbB-2,ErbB-3和ErbB-4的ErbB家族),II类RTK(例如,胰岛素受体家族包括INSR,IGF-1R和IRR),III类RTK(例如,血小板衍生生长因子(PDGF)受体家族,包括PDGFR-α,PDGFR-β,CSF-1R,KIT/SCFR和FLK2/FLT3),IV类RTK(例如,成纤维细胞生长因子(FGF)受体家族,包括FGFR-1,FGFR-2,FGFR-3和FGFR-4),V类RTK(例如,血管内皮生长因子(VEGF)受体家族,包括VEGFR1,VEGFR2和VEGFR3),VI类RTK(例如肝细胞生长因子(HGF)受体家族,包括肝细胞生长因子受体(HGFR/MET)和RON),a VII类RTK(例如,原肌球蛋白受体激酶(Trk)受体家族,包括TRKA,TRKB和TRKC),VIII类RTK(例如,ephrin(Eph)受体家族,包括EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB3,EPHB4,EPHB5和EPHB6),IX类RTK(例如,AXL受体家族如AXL,MER和TRYO3),X类RTK(例如,LTK受体家族如LTK和ALK),XI类RTK(例如,TIE受体家族如TIE和TEK),XII类RTK(例如ROR受体家族ROR1和ROR2),XIII类RTK(例如,盘状结构域受体(DDR)家族如DDR1和DDR2),XIV类RTK(例如RET受体家族如RET),XV类RTK(例如KLG受体家族,包括PTK7),XVI类RTK(例如,RYK受体家族包括Ryk),XVII类RTK(例如,MuSK受体家族如MuSK),CD47,CD70,NKG2D,或其任何衍生物,变体或片段。
在一些实施方案中,增强受体可结合的膜蛋白可包含催化受体(例如受体酪氨酸激酶(RTK))或其任何衍生物,变体或片段的至少一个细胞外区域(例如,配体结合结构域),或包含以这些片段作为抗原的抗体可变区的片段。在一些实施方案中,所述增强受体可结合的膜蛋白包含I类RTK(例如,包括EGFR的表皮生长因子(EGF)受体家族;包括ErbB-2,ErbB-3和ErbB-4的ErbB家族),II类RTK(例如,胰岛素受体家族包括INSR,IGF-1R和IRR),III类RTK(例如,血小板衍生生长因子(PDGF)受体家族,包括PDGFR-α,PDGFR-β,CSF-1R,KIT/SCFR和FLK2/FLT3),IV类RTK(例如,成纤维细胞生长因子(FGF)受体家族,包括FGFR-1,FGFR-2,FGFR-3和FGFR-4),V类RTK(例如,血管内皮生长因子(VEGF)受体家族,包括VEGFR1,VEGFR2和VEGFR3),VI类RTK(例如肝细胞生长因子(HGF)受体家族,包括肝细胞生长因子受体(HGFR/MET)和RON),a VII类RTK(例如,原肌球蛋白受体激酶(Trk)受体家族,包括TRKA,TRKB和TRKC),VIII类RTK(例如,ephrin(Eph)受体家族,包括EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB3,EPHB4,EPHB5和EPHB6),IX类RTK(例如,AXL受体家族如AXL,MER和TRYO3),X类RTK(例如,LTK受体家族如LTK和ALK),XI类RTK(例如,TIE受体家族如TIE和TEK),XII类RTK(例如ROR受体家族ROR1和ROR2),XIII 类RTK(例如,盘状结构域受体(DDR)家族如DDR1和DDR2),XIV类RTK(例如RET受体家族如RET),XV类RTK(例如KLG受体家族,包括PTK7),XVI类RTK(例如,RYK受体家族包括Ryk),XVII类RTK(例如,MuSK受体家族如MuSK),CD47,CD70,NKG2D,或其任何衍生物,变体或片段。
在一些实施方案中,增强受体可结合的膜蛋白包含RTK或其任何衍生物,变体或片段的增强受体可以结合包含任何合适的RTK配体或其任何衍生物、变体或片段的抗原,或包含以这些片段作为抗原的抗体可变区的片段。RTK配体的非限制性实例包括生长因子,细胞因子和激素。生长因子包括,例如,表皮生长因子家族的成员(例如,表皮生长因子或EGF,结合肝素的EGF样生长因子或HB-EGF,转化生长因子-α或TGF-α,双调蛋白或AR,表皮调节素或EPR,epigen,betacellulin或BTC,神经调节蛋白-1或NRG1,神经调节蛋白-2或NRG2,神经调节蛋白-3或NRG3,神经调节蛋白-4或NRG4),成纤维细胞生长因子家族(如FGF1,FGF2,FGF3,FGF4,FGF5,FGF6,FGF7,FGF8,FGF9,FGF10,FGF11,FGF12,FGF13,FGF14,FGF15/19,FGF16,FGF17,FGF18,FGF20,FGF21和FGF23),血管内皮生长因子家族(如VEGF)-A,VEGF-B,VEGF-C,VEGF-D和PIGF)和血小板衍生的生长因子家族(例如,PDGFA,PDGFB,PDGFC和PDGFD)。激素包括,例如,胰岛素/IGF/松弛素家族的成员(例如,胰岛素,胰岛素样生长因子,松弛素家族肽,包括松弛素1,松弛素2,松弛素3,莱迪希细胞特异性胰岛素样肽(基因INSL3),早期胎盘胰岛素样肽(ELIP)(基因INSL4),胰岛素样肽5(基因INSL5)和胰岛素样肽6)。
在一些实施方案中,增强受体可结合的膜蛋白至少包含催化受体的细胞外区域(例如,配体结合结构域),例如受体苏氨酸/丝氨酸激酶(RTSK),或其任何衍生物,变体或片段,或包含以这些片段作为抗原的抗体可变区的片段。所述增强受体可结合的膜蛋白可包含I型RTSK,II型RTSK或其任何衍生物,变体或片段。增强受体可包含I型受体,或其任何衍生物,变体或片段,选自:ALK1(ACVRL1),ALK2(ACVR1A),ALK3(BMPR1A),ALK4(ACVR1B),ALK5(TGFβR1),ALK6(BMPR1B)和ALK7(ACVR1C)。增强受体可包含II型受体,或其选自下组的任何衍生物,变体或片段:TGFβR2,BMPR2,ACVR2A,ACVR2B和AMHR2(AMHR)。在一些实施方案中,增强受体包含TGF-β受体或其任何衍生物,变体或片段。
包含RTSK或其任何衍生物,变体或片段的所述增强受体可结合的膜蛋白可以结合包含任何合适的RTSK配体或其任何衍生物,变体或片段的抗原,或包含以这些片段作为抗原的抗体可变区的片段。
增强受体可包含引发免疫细胞激活信号的共刺激分子的细胞内结构域(ICD)。共刺激分子可以结合配体。在一些情况下,共刺激分子可以被配体响应蛋白激活。在一些实施方案中,共刺激分子可用于调节免疫细胞中的增殖和/或存活信号。在一些实施方案中,ICD是共刺激分子的细胞内结构域,所述共刺激分子选自MHC I类蛋白,MHC II类蛋白,TNF受体蛋白,免疫球蛋白样蛋白,细胞因子受体,整联蛋白,信号传导淋巴细胞活化分子(SLAM蛋白),活化的NK细胞受体,BTLA或Toll配体受体。在一些实施方案中,共刺激分子或共刺激结构域包含选自下组的分子的信号传导结构域:2B4/CD244/SLAMF4,4-1BB/TNFSF9/CD137,B7-1/CD80,B7-2/CD86,B7-H1/PD-L1,B7-H2,B7-H3,B7-H4,B7-H6,B7-H7,BAFF R/TNFRSF13C,BAFF/BLyS/TNFSF13B,BLAME/SLAMF8,BTLA/CD272,CD100(SEMA4D),CD103,CD11a,CD11b,CD11c,CD11d,CD150,CD160(BY55),CD18,CD19,CD2,CD200,CD229/SLAMF3,CD27配体/TNFSF7,CD27/TNFRSF7,CD28,CD29,CD2F-10/SLAMF9,CD3,CD30配体/TNFSF8,CD30/TNFRSF8,CD300a/LMIR1,CD4,CD40配体/TNFSF5,CD40/TNFRSF5,CD48/SLAMF2,CD49a,CD49D,CD49f,CD5,CD53,CD58/LFA-3,CD69,CD7,CD8α,CD8β,CD82/Kai-1,CD84/SLAMF5,CD90/Thy1,CD96,CDS,CEACAM1,CRACC/SLAMF7,CRTAM,CTLA-4,DAP12,Dectin-1/CLEC7A,DNAM1(CD226),DPPIV/CD26,DR3/TNFRSF25,EphB6,GADS,Gi24/VISTA/B7-H5,GITR配体/TNFSF18,GITR/TNFRSF18,HLA I类,HLA-DR,HVEM/TNFRSF14,IA4,ICAM-1,ICOS/CD278,Ikaros,IL2Rβ,IL2Rγ,IL7Rα,IL-12R,整合素α4/CD49d,整合素α4β1,整合素α4β7/LPAM-1,IPO-3,ITGA4,ITGA6,ITGAD,ITGAE,ITGAL,ITGAM,ITGAX,ITGB1,ITGB2,ITGB7,KIRDS2,LAG-3,LAT,LIGHT/TNFSF14,LTBR,Ly108,Ly9(CD229),淋巴细胞功能相关抗原-1(LFA-1),淋巴毒素-α/TNF-β,NKG2C,NKG2D,NKp30,NKp44,NKp46,NKp80(KLRF1),NTB-A/SLAMF6,OX40配体/TNFSF4,OX40/TNFRSF4,PAG/Cbp,PD-1,PDCD6,PD-L2/B7-DC,PSGL1,RELT/TNFRSF19L,SELPLG(CD162),SLAM(SLAMF1),SLAM/CD150,SLAMF4(CD244),SLAMF6(NTB)-A),SLAMF7,SLP-76,TACI/TNFRSF13B,TCL1A,TCL1B,TIM-1/KIM-1/HAVCR,TIM-4,TL1A/TNFSF15,TNF RII/TNFRSF1B,TNF-α,TRANCE/RANKL,TSLP,TSLP R,VLA1和VLA-6。
增强受体的ECD和ICD可以通过跨膜结构域连接,例如通过跨膜区段连接。在一些实施方案中,跨膜区段包含多肽。跨膜多肽可具有任何合适的多肽序列。在一些情况下,跨膜多肽包含内源或野生型跨膜蛋白的跨膜部分的多肽序列。在一些实施方案中,跨膜多肽包含具有至少1个(例如,至少2,3,4,5,6,7,8,9,10或更多个)氨基酸取代,缺失和多肽 的多肽序列。插入与内源或野生型跨膜蛋白的跨膜部分相比。在一些实施方案中,跨膜多肽包含非天然多肽序列,例如多肽接头的序列。多肽接头可以是柔性的或刚性的。多肽接头可以是结构化的或非结构化的。在一些实施方案中,跨膜多肽将来自ECD的信号传递至ICD,例如指示配体结合的信号。在一些实施方案中,ECD包含跨膜结构域。在一些实施方案中,ICD包含跨膜结构域。
在一些实施例中ICD可以介导免疫细胞中产生免疫细胞活化信号(或称免疫细胞激活信号)。在一些实施方案中,免疫细胞活化信号由活化因子介导。激活因子可以是免疫调节分子。激活因子可以结合,激活或刺激T细胞或其他免疫细胞以调节它们的活性。在一些实施方案中,激活因子可以从免疫细胞分泌。活化因子可以是,例如,可溶性细胞因子,可溶性趋化因子或生长因子分子。可介导免疫细胞活化的活化因子的非限制性实例包括可溶性细胞因子,例如IL-1,IL-2,IL-6,IL-7,IL-8,IL-10,IL-12,IL。-15,IL-21,肿瘤坏死因子(TNF),转化生长因子(TGF),干扰素(IFN)或其任何功能片段或变体。
免疫细胞激活信号可包括或导致经修饰的免疫细胞(例如,经修饰的TIL或经修饰的T细胞)的克隆扩增;通过修饰的免疫细胞(例如,修饰的TIL或修饰的T细胞)释放细胞因子;修饰的免疫细胞(例如,修饰的TIL或修饰的T细胞)的细胞毒性;修饰的免疫细胞(例如,修饰的TIL或修饰的T细胞)的增殖;修饰的免疫细胞(例如,修饰的TIL或修饰的T细胞)的分化,去分化或转分化;运动和/或运输经修饰的免疫细胞(例如,修饰的TIL或修饰的T细胞);修饰的免疫细胞(例如,修饰的TIL或修饰的T细胞)的耗尽和/或再激活;通过修饰的免疫细胞(例如,修饰的TIL或修饰的T细胞)释放其他细胞间分子,代谢物,化学化合物或其组合。
在一些实施方案中,免疫细胞活化信号包括或导致免疫细胞的克隆扩增。克隆扩增可包括由免疫细胞产生的子细胞的产生。由克隆扩增产生的子细胞可包含增强受体。修饰的免疫细胞的克隆扩增可以大于缺乏增强受体的可比免疫细胞的克隆扩增。经修饰的免疫细胞的克隆扩增相比于缺乏增强受体的可比免疫细胞可为约5倍至约10倍,约10倍至约20倍,约20倍至约30倍,约30倍至约40倍,约40倍至约50倍,约50倍至约60倍,约60倍至约70倍,约70倍至约80倍,约80倍至约90倍,约90倍至约100倍,约100倍至约200倍,约200倍至约300倍,约300倍至约400倍,约400倍至约500倍,约500倍至约600倍,或约600倍至约700倍。在一些实施方案中,确定克隆扩增可以包括定量免疫细胞的数量,例如在有和没有增强受体的情况下以及在配体与增强受体结合后。可以通过多种技术实现对许多免疫细胞的定量,其非限制性实例包括流式细胞术,台盼蓝排除和血细胞计数。
在一些实施方案中,免疫细胞活化信号包含或导致免疫细胞释放细胞因子。在一些实施方案中,免疫细胞活性包含或导致细胞间分子,代谢物,化学化合物或其组合的释放。修饰的免疫细胞释放的细胞因子可包括释放IL-1,IL-2,IL-4,IL-5,IL-6,IL-13,IL-17,IL-21,IL-22,IFNγ,TNFα,CSF,TGFβ,颗粒酶等。在一些实施方案中,细胞因子释放可使用酶联免疫吸附测定(ELISA),流式细胞术,蛋白质印迹等定量。修饰的免疫细胞的细胞因子释放可以大于缺乏增强受体的可比免疫细胞的细胞因子释放。本文提供的经修饰的免疫细胞可产生与缺乏增强受体的可比免疫细胞相比为约1倍,2倍,3倍,4倍,5倍,6倍,7倍,8倍,9倍,10倍,11倍,12倍,13倍,14倍,15倍,20倍,30倍,40倍,50倍,60倍,70倍,80倍,90倍,100倍,150倍,200倍,250倍,或超过300倍细胞因子释放。当增强受体与配体结合并且经修饰的免疫细胞与靶细胞上存在的新抗原结合时,与缺乏增强受体(例如,未修饰的)的可比免疫细胞相比,经修饰的免疫细胞可表现出增加的细胞因子分泌。在一些实施方案中,分泌的细胞因子是IFNγ或IL-2。在一些实施方案中,细胞因子释放可以在体外或体内定量。
在一些实施方案中,免疫细胞活化信号包含或导致免疫细胞产生细胞毒性。在一些情况下,本文提供的经修饰的免疫细胞的细胞毒性可用于杀死靶细胞。表达增强受体的免疫细胞或免疫细胞群可以诱导靶细胞的死亡。杀死靶细胞可用于多种应用,包括但不限于治疗其中需要消除细胞群或希望抑制其增殖的疾病或病症。细胞毒性还可以指免疫细胞释放细胞毒性细胞因子,例如IFNγ或颗粒酶。在一些情况下,本文提供的经修饰的免疫细胞可以改变(i)细胞毒素的释放,例如穿孔素,颗粒酶和颗粒溶素和/或(ii)通过T细胞和靶细胞之间的Fas-Fas配体相互作用诱导细胞凋亡。在一些实施方案中,细胞毒性可通过细胞毒性测定来定量,包括共培养测定,ELISPOT,铬释放细胞毒性测定等。本文提供的经修饰的免疫细胞的细胞毒性可大于缺乏增强受体的可比免疫细胞的细胞毒性。与缺乏增强受体的可比免疫细胞(例如,未修饰的)相比,当增强受体与配体结合并且经修饰的免疫细胞与靶标上存在的新抗原结合时,修饰的免疫细胞可表现出针对靶细胞的增加的细胞毒性。与缺乏增强受体的可比免疫细胞相比,本发明的经修饰的免疫细胞对靶细胞的细胞毒性可多约5%,10%,15%,20%,25%,30%,35%,40%,45%,50%,55%,60%,65%,70%,75%,80%,85%,90%,95%,100%,125%,150%,175%或200%。本发明的经修饰的免疫细胞可诱导靶细胞死亡,其诱导的靶细胞死亡比没有所述修饰的可比免疫细胞多至少5%,10%,15%,20%,25%,30%,35%,40%,45%,50%,55%,60%,65%,70%,75%,80%,85%,90%,95%,100%,125%,150%,175%或200%。在一些实施方案中,本文提供的免疫细胞可在靶细胞中诱导凋亡,所述靶细胞在其表面上展示 靶表位(例如,新抗原)。在一些实施方案中,细胞毒性可以在体外或体内测定。在一些实施方案中,确定细胞毒性可以包括在施用本文提供的修饰的免疫细胞之后确定与施用之前的疾病水平相比的疾病水平。在一些实施方案中,确定细胞毒性可包括确定施用本文提供的修饰的免疫细胞后的疾病水平和施用缺乏增强受体的可比免疫细胞后的疾病水平。
在一些实施方案中,免疫细胞活化信号包含或导致免疫细胞的增殖。免疫细胞的增殖可以指免疫细胞的扩增。免疫细胞的增殖可以指免疫细胞的表型变化。本公开的经修饰的免疫细胞的增殖可以大于缺乏增强受体的可比免疫细胞的增殖。本文提供的经修饰的免疫细胞的增殖可为缺乏增强受体的科比免疫细胞的约5倍至约10倍,约10倍至约20倍,约20倍至约30倍,约30倍至约40倍,约40倍至约50倍,约50倍至约60倍,约60倍至约70倍,约70倍至约80倍,约80倍至约90倍,约90倍至约100倍,约100倍至约200倍,约为200倍至约300倍,约300倍至约400倍,约400倍至约500倍,约500倍至约600倍,或约600倍至约700倍。在一些实施方案中,可以通过定量免疫细胞的数量来确定增殖。量化许多免疫细胞可包括流式细胞术,台盼蓝排除法和/或血细胞计数法。也可以通过免疫细胞的表型分析来确定增殖。
在一些实施方案中,免疫细胞活化信号可包括或导致免疫细胞的分化,去分化或转分化。免疫细胞的分化,去分化或转分化可以通过流式细胞术评估细胞表面上分化,去分化或转分化的标志物的表型表达来确定。在一些实施方案中,与缺乏增强受体的可比免疫细胞相比,本文提供的经修饰的免疫细胞具有增加的分化能力。在一些实施方案中,与缺乏增强受体的可比免疫细胞相比,本文提供的经修饰的免疫细胞具有增加的去分化能力。在一些实施方案中,与缺乏增强受体的可比免疫细胞相比,本文提供的经修饰的免疫细胞具有增加的去分化能力。在一些实施方案中,与缺乏增强受体的可比免疫细胞相比,本文提供的经修饰的免疫细胞具有更大的转分化能力。
在一些实施方案中,免疫细胞活化信号可包括或导致免疫细胞的运动和/或运输。在一些实施方案中,可以通过定量免疫细胞定位至靶位点来确定运动。例如,本文提供的修饰的免疫细胞可以在施用后在靶位点定量,例如在不是靶位点的位点。可以通过分离病变并定量包含增强受体的许多免疫细胞(例如肿瘤浸润淋巴细胞)来进行定量。包含增强受体的免疫细胞的运动和/或运输可以大于缺乏增强受体的可比免疫细胞的运动和/或运输。在一些实施方案中,在靶位点(例如肿瘤病变)处包含增强受体的免疫细胞的数量可以是缺乏增强受体的可比免疫细胞的约5倍,10倍,15倍,20倍,25倍,30倍,35倍或40倍。也可以使用transwell迁移测定在体外确定贩运。在一些实施方案中,在靶位点处包含增强 受体的免疫细胞的数量,例如在transwell迁移测定中,可以是缺乏增强受体的可比免疫细胞的数量的约5倍,10倍,15倍,20倍,25倍,30倍,35倍或40倍。
在一些实施方案中,免疫细胞活化信号可包括或导致免疫细胞的耗尽和/或活化。可以通过流式细胞术或显微镜分析的表型分析来确定免疫细胞的耗尽和/或活化。例如,定量和/或定性地确定耗尽标记物的表达水平,所述耗尽标记物例如程序性细胞死亡蛋白1(PD1),淋巴细胞活化基因3蛋白(LAG3),2B4,CD160,Tim3和具有免疫球蛋白和ITIM结构域的T细胞免疫受体(TIGIT)。在某些情况下,免疫细胞(如T细胞)会以分层方式失去效应功能并变得疲惫不堪。由于疲劳,IL-2产生和细胞因子表达等功能以及高增殖能力可能丧失。精疲力竭也可能是IFNγ,TNF和趋化因子的产生以及脱颗粒的缺陷。本文提供的经修饰的免疫细胞的耗尽或活化可以大于缺乏增强受体的可比免疫细胞的耗尽或活化。在一些实施方案中,本文提供的免疫细胞与缺乏增强受体的可比免疫细胞相比可经历增加至少约1倍,2倍,3倍,4倍,5倍,6倍,7倍,8倍,9倍,10倍,11倍,12倍,13倍,14倍,15倍,20倍,30倍,40倍,50倍,60倍,70倍,80倍,90倍,100倍,150倍,200倍,250倍或超过300倍的耗尽或活化。在一些实施方案中,本文提供的包含的免疫细胞与缺乏增强受体的可比免疫细胞相比可经历减少至少约1倍,2倍,3倍,4倍,5倍,6倍,7倍,8倍,9倍,10倍,11倍,12倍,13倍,14倍,15倍,20倍,30倍,40倍,50倍,60倍,70倍,80倍,90倍,100倍,150倍,200倍,250倍或超过300倍的耗尽或活化。
在一些实施方案中,靶细胞与增强受体的结合可在经增强受体修饰的免疫细胞产生免疫细胞活化信号。
在一些实施方案中,在增强受体与配体结合后,与缺乏增强受体的免疫细胞相比,经增强受体修饰的免疫细胞(例如,经修饰的TIL或经修饰的T细胞)表现出增强的新抗原结合。
在一些实施例中,经增强受体修饰的免疫细胞(如TIL,新抗原反应性T细胞,CAR-T,TCR-T,NK等),与未经增强修饰修饰的免疫细胞(分别对应如前述TIL,新抗原反应性T细胞,CAR-T,TCR-T,NK等)相比,可以在一定程度上更好的克服来自肿瘤微环境的对免疫细胞的抑制信号,该抑制信号可以来自该增强受体胞外结构域的配体或抗原,也可以来自该配体或抗原之外的其他肿瘤微环境对免疫细胞的抑制信号。
在一些实施例中,增强受体的ECD是PD1或PDL1单抗,ICD是任意某种共刺激分子,其可以在一定程度上有效克服的肿瘤抑制信号不止于PDL1,还可以包括来自CD47, TIM-3配体如Galectin-9,TIGIT配体如CD155和CD122或PVR,CTLA-4配体如B7对免疫细胞的抑制信号。
在一些实施例中,若增强受体的ECD是SIRPα或CD47单抗,ICD是任意某种共刺激分子,其可以在一定程度上有效克服的肿瘤抑制信号不止于来自CD47,还可以包括来自PDL1,TIM-3配体如Galectin-9,TIGIT配体如CD155和CD122或PVR,CTLA-4配体如B77对免疫细胞的抑制信号。
在一些实施例中,增强受体的ECD是TIM-3配体单抗如Galectin-9单抗或TIM-3单抗,ICD是任意某种共刺激分子,其可以在一定程度上有效克服的肿瘤抑制信号不止于来自TIM-3配体如Galectin-9,还可以包括来自PDL1,TIGIT配体如CD155和CD122或PVR,CTLA-4配体如B77对免疫细胞的抑制信号。
在一些实施例中,增强受体的ECD是TIGIT或其配体的单抗如CD155单抗或CD122单抗或PVR单抗,ICD是任意某种共刺激分子,其可以在一定程度上有效克服的肿瘤抑制信号不止于来自TIGIT配体如CD155和CD122或PVR,还可以包括来自PDL1,TIM-3配体如Galectin-9,CTLA-4配体如B77对免疫细胞的抑制信号。
在一些实施例中,增强受体的ECD是VISTA,ICD是任意某种共刺激分子,其可以在一定程度上有效克服的肿瘤抑制信号不止于来自VISTA配体;若增强受体的ECD是CTLA-4,其可以在一定程度上有效克服的肿瘤抑制信号不止于来自CTLA-4配体如B7,还可以包括来自PDL1,CD47,TIM-3配体如Galectin-9,TIGIT配体如CD155和CD122或PVR,CTLA-4配体如B77对免疫细胞的抑制信号。
在一些实施例中,经aBA-CAR和增强受体修饰的T细胞还带有人工(或称外源性)T细胞受体(TCR)或另一种嵌合抗原受体CAR,当TCR或CAR能识别靶细胞时,经增强受体修饰的T细胞比未经增强受体修饰的T细胞有更强的免疫细胞活化功能;当人工TCR或另一种CAR都不能能识别靶细胞时,经增强受体修饰的T细胞并不比未经增强受体修饰的T细胞具有更强的免疫细胞活化功能。
表现出与新抗原特异性结合的T细胞受体(TCR)复合物可以是内源性TCR复合物或外源性TCR复合物。修饰的免疫细胞的TCR复合物(例如内源或外源)可赋予免疫细胞的抗原结合特异性(例如,新抗原结合)。
在一个方面,本公开内容提供了特异性结合新抗原的经修饰的免疫细胞,其中所述经修饰的免疫细胞包含:(a)嵌合刺激分子,其包含与新抗原结合的多肽细胞外结构域(PED),其中PED与介导免疫细胞活化信号的共刺激分子的细胞内结构域(ICD)融合,并且其中嵌合刺激分子与新抗原的结合在修饰的免疫细胞中产生免疫细胞活化信号,和 (b)aBA-CAR,其包含(i)能够结合助推抗原相互作用结构域;(ii)跨膜结构域;(iii)细胞内信号传导结构域。在一些实施方案中,PED可以是未修饰的TIL的表面蛋白的细胞外结构域。在一些实施方案中,PED的实例包括抗体,以及其衍生物,变体和片段。
在一个实施例中,本公开内容提供了特异性结合新抗原或肿瘤相关抗原(TAA)或癌睾抗原或病毒(如HPV、EBV)来源抗原的经修饰的免疫细胞,其中所述经修饰的免疫细胞包含:(a)可特异结合新抗原的天然TCR或经基因工程改造的外源性TCR;(b)包含蛋白质的细胞外结构域(ECD)的增强受体,其中ECD融合至介导免疫细胞激活信号的共刺激分子的细胞内结构域(ICD),并且其中增强受体与配体在修饰的免疫细胞中产生免疫细胞活化信号而不是免疫细胞灭活信号,和(c)aBA-CAR,其包含(i)能够结合助推抗原相互作用结构域;(ii)跨膜结构域;(iii)细胞内信号传导结构域;在上述a、b、c三者中,c是不可或缺的,在某些实施例中,b或a可以只存在其一;在某些实施例中,a、b、c三者共存。
在一个实施例中,本公开提供了特异性结合新抗原的经修饰的肿瘤浸润淋巴细胞(TIL),其中所述经修饰的免疫细胞包含:(a)可特异结合新抗原的天然TCR;(b)包含蛋白质的细胞外结构域(ECD)的增强受体。ECD与介导免疫细胞活化信号的共刺激分子的细胞内结构域(ICD)融合,并且其中将分子转换成配体在修饰的TIL中产生免疫细胞活化信号而不是免疫细胞灭活信号,和(c)aBA-CAR,其包含(i)能够结合助推抗原相互作用结构域;(ii)跨膜结构域;(iii)细胞内信号传导结构域。在上述a、b、c三者中,c是不可或缺的,在某些实施例中,b或a可以只存在其一;在某些实施例中,a、b、c三者共存,并将三者共存的细胞称为超级TIL(Super TIL,STIL)。
在一个方面,本公开内容提供了过表达细胞因子的经修饰的免疫细胞,例如趋化因子,其中免疫细胞是(i)肿瘤浸润淋巴细胞(TIL);(ii)间质肿瘤浸润淋巴细胞(sTIL);或(iii)表现出与抗原特异性结合的T细胞。过表达趋化因子的经修饰的免疫细胞可以是本文提供的任何经修饰的免疫细胞。
细胞因子是指细胞释放的蛋白质(例如,趋化因子,干扰素,淋巴因子,白细胞介素和肿瘤坏死因子),其可以影响细胞行为。细胞因子由多种细胞产生,包括免疫细胞如巨噬细胞,B淋巴细胞,T淋巴细胞和肥大细胞,以及内皮细胞,成纤维细胞和各种基质细胞。给定的细胞因子可以由一种以上的细胞产生。细胞因子可参与产生全身或局部免疫调节作用。
某些细胞因子可以作为促炎细胞因子起作用。促炎细胞因子是指参与诱导或扩增炎症反应的细胞因子。促炎细胞因子可以与免疫系统的各种细胞(例如嗜中性粒细胞和白细胞)一起产生免疫应答。某些细胞因子可以起抗炎细胞因子的作用。抗炎细胞因子是指参 与减少炎症反应的细胞因子。在一些情况下,抗炎细胞因子可以调节促炎细胞因子反应。一些细胞因子可以作为促炎细胞因子和抗炎细胞因子起作用。某些细胞因子,例如趋化因子,可以在趋化性中起作用。趋化因子可以在附近的响应细胞中诱导定向趋化性。
在一些实施方案中,具有促炎和/或趋化功能的细胞因子的表达可在免疫细胞中上调。上调具有促炎和/或趋化功能的细胞因子的表达可用于例如在免疫疗法中刺激针对靶细胞的免疫应答。
可由本文提供的免疫细胞过表达的细胞因子的实例包括但不限于淋巴因子,单核因子和传统多肽激素。细胞因子中包括生长激素,如人生长激素,N-甲硫氨酰人生长激素和牛生长激素;甲状旁腺激素;甲状腺素;胰岛素;胰岛素原;松弛素;松弛素原;糖蛋白激素,如促卵泡激素(FSH),促甲状腺激素(TSH)和黄体生成素(LH);肝生长因子;成纤维细胞生长因子;催乳素;胎盘催乳素;肿瘤坏死因子-α;mullerian抑制物质;小鼠促性腺激素相关肽;抑制素;激活素;血管内皮生长因子;整合素;血小板生成素(TPO);神经生长因子如NGF-α;血小板生长因子;转化生长因子(TGFs),如TGF-α,TGF-β,TGF-β1,TGF-β2和TGF-β3;胰岛素样生长因子-I和-II;促红细胞生成素(EPO);FLT-3L;干细胞因子(SCF);骨诱导因素;干扰素(IFN),如IFN-α,IFN-β,IFN-γ;集落刺激因子(CSFs),如巨噬细胞-CSF(M-CSF);粒细胞-巨噬细胞-CSF(GM-CSF);粒细胞-CSF(G-CSF);巨噬细胞刺激因子(MSP);白细胞介素(ILs),如IL-1,IL-1a,IL-1b,IL-1RA,IL-18,IL-2,IL-3,IL-4,IL-5,IL-6,IL-7,IL-8,IL-9,IL-10,IL-11,IL-12,IL-13,IL-14,IL-15,IL-16,IL-17,IL-20;肿瘤坏死因子如CD154,LT-β,TNF-α,TNF-β,4-1BBL,APRIL,CD70,CD153,CD178,GITRL,LIGHT,OX40L,TALL-1,TRAIL,TWEAK,TRANCE;和其他多肽因子包括LIF,制瘤素M(OSM)和KIT配体(KL)。细胞因子受体是指结合细胞因子的受体蛋白。细胞因子受体可以是膜结合的和可溶的。
在一些实施方案中,过表达的细胞因子是白细胞介素(IL-1)家族成员(例如配体),IL-1受体家族成员,白细胞介素-6(IL-6)家族成员(例如配体),IL-6受体,白细胞介素-10(IL-10)家族成员(例如配体),IL-10受体,白细胞介素-12(IL-12)家族成员(例如配体),IL-12受体,白细胞介素-17(IL-17)家族成员(例如配体)或IL-17受体。
在一些实施方案中,过表达的细胞因子是白细胞介素-1(IL-1)家族成员或相关蛋白;肿瘤坏死因子(TNF)家族成员或相关蛋白;干扰素(IFN)家族成员或相关蛋白质;白细胞介素-6(IL-6)家族成员或相关蛋白;或趋化因子或相关蛋白。在一些实施方案中,细胞因子选自IL18,IL18BP,IL1A,IL1B,IL1F10,IL1F3/IL1RA,IL1F5,IL1F6,IL1F7,IL1F8,IL1RL2,IL1F9,IL33,BAFF/BLyS/TNFSF138,4-1BBL,CD153/CD30L。/TNFSF8,CD40LG, CD70,Fas配体/FASLG/CD95L/CD178,EDA-A1,TNFSF14/LIGHT/CD258,TNFA,LTA/TNFB/TNFSF1,LTB/TNFC,CD70/CD27L/TNFSF7,TNFSF10/TRAIL/APO-2L(CD253),RANKL/OPGL/TNFSF11(CD254),TNFSF12,TNF-α/TNFA,TNFSF13,TL1A/TNFSF15,OX-40L/TNFSF4/CD252,CD40L/CD154/TNFSF5,IFNA1,IFNA10,IFNA13,IFNA14,IFNA2,IFNA4,IFNA7,IFNB1,IFNE,IFNG,IFNZ,IFNA8,IFNA5/IFNaG,IFNω/IFNW1,CLCF1,CNTF,IL11,IL31,IL6,Leptin,LIF,OSM,CCL1/TCA3,CCL11,CCL12/MCP-5,CCL13/MCP-4,CCL14,CCL15,CCL16,CCL17/TARC,CCL18,CCL19,CCL2/MCP-1,CCL20,CCL21,CCL22/MDC,CCL23,CCL24,CCL25,CCL26,CCL27,CCL28,CCL3,CCL3L3,CCL4,CCL4L1/LAG-1,CCL5,CCL6,CCL7,CCL8,CCL9,CX3CL1,CXCL1,CXCL10,CXCL11,CXCL12,CXCL13,CXCL14,CXCL15,CXCL16,CXCL17,CXCL2/MIP-2,CXCL3,CXCL4,CXCL5,CXCL6,CXCL7/Ppbp,CXCL9,IL8/CX CL8,XCL1,XCL2,FAM19A1,FAM19A2,FAM19A3,FAM19A4和FAM19A5。
可以使用多种方法评估细胞因子表达。细胞因子表达可以通过测定经修饰的免疫细胞在其中生长的细胞培养基(例如,体外生产)或从具有经修饰的免疫细胞的受试者获得的血清(例如,体内生产)中一种或多种细胞因子的存在来评估。细胞因子水平可以使用任何合适的测定以各种合适的单位定量,包括浓度。在一些实施方案中,检测细胞因子蛋白。在一些实施方案中,检测细胞因子的mRNA转录物。细胞因子测定的实例包括酶联免疫吸附测定(ELISA),免疫印迹,免疫荧光测定,放射免疫测定,允许平行检测样品中的各种细胞因子的抗体阵列,基于珠子的阵列,定量PCR,微阵列等。其他合适的方法可能包括蛋白质组学方法(2-D凝胶,MS分析等)。
在一些实施方案中,由本文提供的经修饰的免疫细胞过表达的细胞因子是趋化因子。趋化因子可以是例如CC趋化因子,CXC趋化因子,C趋化因子和CX3C趋化因子。在一些实施方案中,由修饰的免疫细胞过表达的趋化因子是CC趋化因子,其选自CCL1,CCL2,CCL3,CCL4,CCL5,CCL6,CCL7,CCL8,CCL9,CCL10,CCL11,CCL12,CCL13,CCL14,CCL15,CCL16,CCL17,CCL18,CCL19,CCL20,CCL21,CCL22,CCL23,CCL24,CCL25,CCL26,CCL27和CCL28。所述趋化因子是选自CXCL1,CXCL2,CXCL3,CXCL4,CXCL5,CXCL6,CXCL7,CXCL8,CXCL9,CXCL10,CXCL11,CXCL12,CXCL13,CXCL14,CXCL15,CXCL16和CXCL17的CXC趋化因子。在一些实施方案中,由修饰的免疫细胞过表达的趋化因子是选自XCL1和XCL2的C趋化因子。在一些实施方案中,免疫细胞过表达的趋化因子是CX3C趋化因子,CX3C趋化因子是CX3CL1。
在一些情况下,本文提供一种免疫细胞,是经过除aBA-CAR修饰之外的基因修饰的NK细胞。
在一些情况下,本文提供一种NK细胞,该NK细胞是经过除aBA-CAR修饰之外的CAR基因修饰的CAR-NK细胞,且这种除aBA-CAR之外的CAR基因修饰赋予了NK细胞特异识别并杀伤靶细胞的特性;所述除aBA-CAR之外的CAR基因修饰可以包括NKG2D的部分结构。
在一些情况下,助推佐剂是由n种本发明的助推性细胞组成的级联放大助推体系,其中所述n为正整数,其中第一级助推性细胞表达第一种助推抗原(BA1),第二级助推性细胞表达第二种助推抗原(BA2)和特异性靶向第一种助推抗原的aBA1-CAR,第三级助推性细胞表达第三种助推抗原(BA3)和特异性靶向第二种助推抗原的aBA2-CAR,……第n级助推性细胞表达第n种助推抗原(BAn)和靶向第n-1级助推抗原的aBA
n-1-CAR,所述第n种助推抗原BAn可以被所述治疗性免疫细胞所识别,并且各级之间的助推抗原互不相同。
在一些情况下,级联放大的多级助推体系的级数n可以是等于1-10000000范围内的任一正整数。
在一些情况下,级联放大的多级助推体系,从第二级开始的助推性细胞均可在体内借助BA-CAR被上一级助推抗原所激活而扩增,不同级的助推性细胞可以是同一类细胞(如均为T细胞,或均为NK细胞),也可以是不同类的细胞,也可以是多种细胞的混合物。
本发明提供了一种免疫细胞治疗佐剂药物组合物,其特征在于,该药物组合物包含本文所述的助推佐剂。
本发明提供了一种免疫细胞治疗药物组合,其特征在于,该药物组合包括本文所述的助推佐剂,以及本发明所述的治疗性免疫细胞,其中将所述治疗性免疫细胞与所述药物组合物在恰当时点的单次或连续多次回输,从而使得所述治疗性免疫细胞可被所述药物组合物中的佐剂激活并且在数量上得到扩增,由此可识别并杀伤靶细胞。
本发明提供了一种治疗癌症的方法,其特征在于,应用了本文所述的免疫细胞治疗佐剂药物组合物或免疫细胞治疗药物组合,具体而言是将所述治疗性免疫细胞与所述免疫细胞治疗佐剂药物在恰当时点的单次或连续多次回输。
在一个方面,本公开内容提供了治疗受试者的癌症的方法,其包括:(a)向受试者施用经修饰的TIL,经修饰的在外周血PBMC经PD1、TIM3、CD137、CD39一种或多 种阳性筛选的T细胞,经修饰的T细胞或经修饰的免疫细胞,其中任一个实施方案中的任一个。这里的方面;(b)在诱导修饰的TIL,修饰的经筛选的T细胞,修饰的T细胞或修饰的免疫细胞对抗靶细胞的细胞毒性的条件下,使表达新抗原的癌症的靶细胞与修饰的TIL,修饰的经筛选的T细胞,修饰的T细胞或修饰的免疫细胞接触,从而诱导癌症靶细胞的死亡。
在一个方面,本公开内容提供了扩增T细胞群的方法,该方法包括:(a)提供T细胞群,其至少包含所述方面的各种实施方案中任一个的经修饰的免疫细胞。本文;(b)将T细胞群暴露于助推抗原以实现T细胞群的扩增。
在一个方面,本公开内容提供了扩增T细胞群的方法,其包括:(a)将编码aBA-CAR的核酸引入T细胞群中,从而产生表达aBA-CAR的细胞或细胞群,其中aBA-CAR包含(i)与CAR所特异识别的抗原相互作用的结构域;(ii)跨膜结构域;(iii)细胞内信号传导结构域;(b)使表达aBA-CAR的细胞群与助推抗原接触,从而产生扩增和/或活化的免疫细胞群。其中,所述抗原并非由肿瘤靶细胞所特异表达。
在一个方面,本公开内容提供了包含一种或多种编码以下一种或多种的多核苷酸的组合物:(a)增强受体,其中所述增强受体包含蛋白质的细胞外结构域(ECD),其中ECD与介导免疫细胞激活信号的共刺激蛋白的细胞内结构域(ICD)融合;(b)抗原特异性T细胞受体复合物,或其一种或多种组分。
在一个方面,本公开提供了包含一种或多种编码以下一种或多种的多核苷酸的组合物:(a)抗原特异性T细胞受体复合物,或其一种或多种组分;(b)aBA-CAR,其包含(i)能够结合助推抗原相互作用结构域;(ii)跨膜结构域;(iii)细胞内信号传导结构域。
在一个方面,本公开内容提供了包含一种或多种编码以下一种或多种的多核苷酸的组合物:(a)增强受体,其中所述增强受体包含蛋白质的细胞外结构域(ECD),其中所述ECD与介导免疫细胞激活信号的共刺激蛋白的细胞内结构域(ICD)融合;(b)aBA-CAR,其包含(i)能够结合助推抗原相互作用结构域;(ii)跨膜结构域;(iii)细胞内信号传导结构域。
在一个方面,本公开内容提供了包含一种或多种编码以下一种或多种的多核苷酸的组合物:(a)增强受体,其中所述增强受体包含蛋白质的细胞外结构域(ECD),其中所述ECD与介导免疫细胞激活信号的共刺激蛋白的细胞内结构域(ICD)融合;(b)抗原特异性T细胞受体复合物,或其一种或多种组分;(c)aBA-CAR,其包含(i)能够结合助推抗原相互作用结构域;(ii)跨膜结构域;(iii)细胞内信号传导结构域。
在本文方面的各种实施方案中,可以与本公开的组合物一起使用的启动子,包括在真核,哺乳动物,非人哺乳动物或人细胞中有活性的启动子。启动子可以是诱导型或组成型活性启动子。或者或另外,启动子可以是组织或细胞特异性的。
合适的真核启动子(即在真核细胞中起作用的启动子)的非限制性实例可包括来自如下来源的启动子:早期巨细胞病毒(CMV),单纯疱疹病毒(HSV)胸苷激酶,早期和晚期SV40,来自逆转录病毒的长末端重复序列(LTR),人延伸因子-1启动子(EF1),一种包含与鸡β活性启动子(CAG)融合的巨细胞病毒(CMV)增强子的杂合构建体,鼠干细胞病毒启动子(MSCV),磷酸甘油酸激酶-1基因座启动子(PGK)和小鼠金属硫蛋白-I。启动子可以是真菌启动子。启动子可以是植物启动子。可以找到植物启动子的数据库(例如,PlantProm)。表达载体还可含有用于翻译起始的核糖体结合位点和转录终止子。表达载体还可以包括用于扩增表达的合适序列。
在本文方面的各种实施方案中,经修饰的免疫细胞可特异性结合新抗原和/或新表位。新抗原和新表位通常是指肿瘤特异性突变,在某些情况下会引发抗肿瘤T细胞反应。例如,可以使用全体外显子测序方法鉴定这些内源性突变(Tran E等人,“基于突变特异性CD4+T细胞在患有上皮癌的患者中的癌症免疫疗法”,Science 344:641-644(2014))。包含增强受体的经修饰的免疫细胞(例如,经修饰的TIL或经修饰的T细胞)可表现出与肿瘤特异性新抗原的特异性结合。由免疫细胞结合的新抗原可以在靶细胞上表达,并且例如由内源基因中的突变编码。在一些情况下,由免疫细胞特异性结合的新抗原或新表位可由突变基因编码。该基因可选自:ABL1,ACO1 1997,ACVR2A,AFP,AKT1,ALK,ALPPL2,ANAPC1,APC,ARID1A,AR,AR-v7,ASCL2,β2Μ,BRAF,BTK,C15ORF40,CDH1,CLDN6,CNOT1,CT45A5,CTAG1B(编码NY-ESO-1),DCT,DKK4,EEF1B2,EEF1DP3,EGFR,EIF2B3,env,EPHB2,ERBB3,ESR1,ESRP1,FAM111B,FGFR3,FRG1B,GAGE1,GAGE 10,GATA3,GBP3,HER2,IDH1,JAK1,KIT,KRAS,LMAN1,MABEB16,MAGEA1,MAGEA10,MAGEA4,MAGEA8,MAGEB 17,MAGEB4,MAGEC1,MEK,MLANA,MLL2,MMP13,MSH3,MSH6,MYC,NDUFC2,NRAS,NY-ESO,PAGE2,PAGE5,PDGFRa,PIK3CA,PMEL,pol蛋白,POLE,PTEN,RAC1,RBM27,RNF43,RPL22,RUNX1,SEC31A,SEC63,SF3B 1,SLC35F5,SLC45A2,SMAP1,SMAP1,SPOP,TFAM,TGFBR2,THAP5,TP53,TTK,TYR,UBR5,VHL和XPOT。在一些实施方案中,基于来自个体的肿瘤样品的遗传谱选择新抗原。在一些实施方案中,可以基于来自个体的肿瘤样品的体细胞突变谱来选择新抗原。
在本文方面的各种实施方案中,修饰的免疫细胞还包含杀灭开关(或称自杀开关)。在严重毒性的情况下,例如高细胞因子血症,可以激活杀灭开关以消除免疫细胞。当免疫系统具有如此强烈的反应以致许多炎性细胞因子被释放时,可能发生这种情况,引发轻微至严重的症状,包括发烧,头痛,皮疹,心跳加速,低血压和呼吸困难。杀灭开关可以是药物诱导杀灭开关。杀灭开关可包含诱导型半胱天冬酶9。
本文方面的各种实施方案包括细胞,例如经修饰的免疫细胞。细胞,例如免疫细胞(例如,包括T细胞和NK细胞的淋巴细胞)可以从受试者获得。受试者的非限制性实例包括人,狗,猫,小鼠,大鼠及其转基因物种。来自可从其获得细胞的受试者的样品的实例包括但不限于皮肤,心脏,肺,肾,骨髓,乳腺,胰腺,肝,肌肉,平滑肌,膀胱,胆囊,结肠,肠,脑,前列腺,食道,甲状腺,血清,唾液,尿液,胃和消化液,眼泪,粪便,精液,阴道液,来自肿瘤组织的间质液,眼液,汗液,粘液,耳垢,油,腺体分泌物,脊髓液,头发,指甲,血浆,鼻拭子或鼻咽清洗,脊髓液,脑脊髓液,组织,咽喉拭子,活检,胎盘液,羊水,脐带血,强力液,腔液,痰液,脓液,微生物群,胎粪,乳房牛奶和/或其他排泄物或身体组织。
在一些情况下,细胞可以是从受试者获得的T细胞群,NK细胞,B细胞等。T细胞可以从许多来源获得,包括PBMC,骨髓,淋巴结组织,脐带血,胸腺组织和来自感染部位,腹水,胸腔积液,脾组织和肿瘤的组织。在一些实施方案中,可以使用任何数量的技术,例如FicollTM分离,从受试者收集的血液单位中获得T细胞。在一个实施方案中,通过单采血液成分术获得来自个体循环血液的细胞。单采血液成分产品通常含有淋巴细胞,包括T细胞,单核细胞,粒细胞,B细胞,其他有核白细胞,红细胞和血小板。可以洗涤通过单采血液成分术收集的细胞以除去血浆部分并将细胞置于合适的缓冲液或培养基中用于后续处理步骤。
在本文的方面中可以使用多种免疫细胞中的任何一种。在一些实施方案中,免疫细胞包括粒细胞,例如asophils,嗜酸性粒细胞和嗜中性粒细胞;肥大细胞;单核细胞可发育成巨噬细胞;抗原呈递细胞,如树突状细胞;和淋巴细胞,如自然杀伤细胞(NK细胞),B细胞和T细胞。在一些实施方案中,免疫细胞是免疫效应细胞。免疫效应细胞是指能够响应刺激而发挥特定功能的免疫细胞。在一些实施方案中,免疫细胞是可以诱导细胞死亡的免疫效应细胞。在一些实施方案中,免疫细胞是淋巴细胞。在一些实施方案中,淋巴细胞是NK细胞。在一些实施方案中,淋巴细胞是T细胞。在一些实施方案中,T细胞是活化的T细胞。T细胞包括幼稚和记忆细胞(例如中枢记忆或TCM,效应记忆或TEM和效应记忆RA或TEMRA),效应细胞(例如细胞毒性T细胞或CTL或Tc细胞),辅助细胞(例 如Th1,Th2,Th3),Th9,Th7,TFH),调节细胞(例如Treg和Tr1细胞),天然杀伤T细胞(NKT细胞),肿瘤浸润淋巴细胞(TIL),淋巴细胞激活的杀伤细胞(LAK),αβΤ细胞,γδΤ细胞和T细胞谱系的类似独特类别。T细胞可分为两大类:CD8+T细胞和CD4+T细胞,基于细胞表面存在蛋白质。表达受试者系统的T细胞可以执行多种功能,包括杀死受感染的细胞和激活或募集其他免疫细胞。CD8+T细胞被称为细胞毒性T细胞或细胞毒性T淋巴细胞(CTL)。表达受试者系统的CTL可参与识别和去除病毒感染的细胞和癌细胞。CTL具有特化的区室或颗粒,其含有引起细胞凋亡的细胞毒素,例如程序性细胞死亡。CD4+T细胞可以细分为四个亚组--Th1,Th2,Th17和Treg,“Th”指的是“T辅助细胞”,尽管可能存在其他亚组。Th1细胞可以协调针对细胞内微生物,特别是细菌的免疫应答。它们可以产生和分泌警报和激活其他免疫细胞的分子,如摄入巨噬细胞的细菌。Th2细胞通过警告B细胞,粒细胞和肥大细胞参与协调针对细胞外病原体(如蠕虫(寄生虫))的免疫应答。Th17细胞可以产生白细胞介素17(IL-17),这是一种激活免疫和非免疫细胞的信号分子。Th17细胞对于募集嗜中性粒细胞很重要。
在一些实施方案中,本文提供的免疫细胞群可以是异质的。在一些实施方案中,使用的细胞可以由CD4和CD8T细胞的异质混合物组成。CD4和CD8细胞可具有循环效应T细胞的表型特征。所述CD4和CD8细胞还可具有效应记忆细胞的表型特征。在一些实施方案中,细胞可以是中枢记忆细胞。
在一些实施方案中,细胞包括外周血单核细胞(PBMC),外周血淋巴细胞(PBL)和其他血细胞亚群,例如但不限于T细胞,天然杀伤细胞,单核细胞,天然杀伤性T细胞,单核细胞前体细胞,造血干细胞或非多能干细胞。在一些情况下,细胞可以是任何免疫细胞,包括任何T细胞,例如肿瘤浸润细胞(TIL),例如CD3+T细胞,CD4+T细胞,CD8+T细胞或任何其他类型的T-细胞。T细胞还可包括记忆T细胞,记忆干T细胞或效应T细胞。T细胞也可以选自大量群体(bulk population),例如,从全血中选择T细胞。T细胞也可以从大量群体中扩增。T细胞也可以偏向特定的群体和表型。例如,T细胞可以偏向某个表型,包括CD45RO(-),CCR7(+),CD45RA(+),CD62L(+),CD27(+),CD28(+)和/或IL-7Rα(+)。可以选择合适的细胞,其包含选自以下列表中的一种或多种标志物:CD45RO(-),CCR7(+),CD45RA(+),CD62L(+),CD27(+),CD28(+)和/或IL。-7Rα(+)。细胞还包括干细胞,例如胚胎干细胞,诱导的多能干细胞,造血干细胞,神经元干细胞和间充质干细胞。细胞可包含任何数量的原代细胞,例如人细胞,非人细胞和/或小鼠细胞。细胞可以是祖细胞。细胞可以来自待治疗的受试者(例如,患者)。细胞可以源自人类供体。宿主细胞可以是由CD45RO(-),CCR7(+),CD45RA(+),CD62L+(L-选择蛋白),CD27+, CD28+和IL-7Rα+组成的干记忆TSCM细胞,所述干记忆细胞也可以表达CD95,IL-2Rβ,CXCR3和LFA-1,并显示出与所述干存储细胞不同的许多功能属性。宿主细胞可以是包含L-选择蛋白和CCR7的中枢记忆TCM细胞,所述中枢记忆细胞可以分泌例如IL-2,但不分泌IFNγ或IL-4。细胞也可以是包含L-选择蛋白或CCR7的效应记忆TEM细胞,并产生例如效应细胞因子如IFNγ和IL-4。
在本文方面的各种实施方案中,免疫细胞包含淋巴细胞。在一些实施方案中,淋巴细胞是天然杀伤细胞(NK细胞)。在一些实施方案中,淋巴细胞是T细胞。T细胞可以从许多来源获得,包括外周血单核细胞,骨髓,淋巴结组织,脾组织,脐带和肿瘤。在一些实施方案中,可以使用任何数量的可用T细胞系。免疫细胞如淋巴细胞(例如细胞毒性淋巴细胞)可以优选是自体细胞,但也可以使用异源细胞。可以使用任何数量的技术,例如Ficoll分离,从受试者收集的血液单位中获得T细胞。来自个体的循环血液的细胞可以通过单采血液成分术或白细胞去除术获得。单采血液成分产品通常含有淋巴细胞,包括T细胞,单核细胞,粒细胞,B细胞,其他有核白细胞,红细胞和血小板。可以洗涤通过单采血液成分术收集的细胞以除去血浆部分,并将细胞置于合适的缓冲液或培养基中,例如磷酸盐缓冲盐水(PBS),用于随后的处理步骤。洗涤后,可将细胞重悬于各种生物相容性缓冲液中,例如不含Ca的无Mg PBS。或者,可以除去单采血液成分样品中不需要的组分,并将细胞直接重悬于培养基中。样品可以由受试者直接提供,或间接通过一个或多个中间体提供,例如样品采集服务提供者或医学提供者(例如医生或护士)。在一些实施方案中,从外周血白细胞中分离T细胞可包括裂解红细胞并通过例如通过例如PERCOL TM梯度离心从外周血白细胞与单核细胞分离。
可以通过阳性或阴性选择技术进一步分离T细胞的特定亚群,例如CD4+或CD8+T细胞。例如,用针对负选择的细胞特有的表面标志物的抗体组合,可以实现T细胞群的阴性选择。一种合适的技术包括通过负磁性免疫粘附进行细胞分选,其利用针对负面选择的细胞上存在的细胞表面标志物的单克隆抗体混合物。例如,为了分离CD4+细胞,单克隆抗体混合物可包括针对CD14,CD20,CD11b,CD16,HLA-DR和CD8的抗体。阴性选择过程可用于产生主要是同质的所需T细胞群。在一些实施方案中,组合物包含两种或更多种(例如2,3,4,5种或更多种)不同种类的T细胞的混合物。
在一些实施方案中,免疫细胞是富集细胞群的成员。可通过任何合适的方法富集一种或多种所需细胞类型,其非限制性实例包括处理细胞群以触发扩增和/或分化成所需细胞类型,治疗以阻止不需要的细胞类型的生长,处理以杀死或裂解不需要的细胞类型,纯化所需细胞类型(例如在亲和柱上纯化以基于一种或多种细胞表面标志物保留所需或不 需要的细胞类型)。在一些实施方案中,富集的细胞群是富含细胞毒性淋巴细胞的细胞群,所述细胞毒性淋巴细胞选自细胞毒性T细胞(也称为细胞毒性T淋巴细胞,CTL,T杀伤细胞,溶细胞性T细胞,CD8+T细胞和杀伤性T细胞),自然杀伤(NK)细胞和淋巴因子激活的杀伤(LAK)细胞。
为了通过阳性或阴性选择分离所需的细胞群,可以改变细胞和表面(例如,珠子等颗粒)的浓度。在某些实施方案中,可能需要显著降低珠子和细胞混合在一起的体积(即,增加细胞浓度),以确保细胞和珠子的最大接触。例如,可以使用20亿个细胞/mL的浓度。在一些实施方案中,使用10亿个细胞/mL的浓度。在一些实施方案中,使用大于1亿个细胞/mL。可以使用1000,1500,2000,2500,3000,3500,4000,4500或5000万个细胞/mL的细胞浓度。在另一个实施方案中,可以使用7500万个,8000万个,8500万个,9000万个,9500万个或1亿个细胞/mL的细胞浓度。在进一步的实施方案中,可以使用1.25亿个或1.5亿个细胞/mL的浓度。使用高浓度可导致细胞产量增加,细胞活化和细胞扩增。
可以使用本公开的系统和方法杀死多种靶细胞。可以应用该方法的靶细胞包括多种细胞类型。靶细胞可以是体外的。靶细胞可以在体内。靶细胞可以离体。靶细胞可以是分离的细胞。靶细胞可以是生物体内的细胞。靶细胞可以是生物体。靶细胞可以是细胞培养物中的细胞。靶细胞可以是一个细胞集合中的一种。靶细胞可以是哺乳动物细胞或源自哺乳动物细胞。靶细胞可以是啮齿动物细胞或源自啮齿动物细胞。靶细胞可以是人细胞或源自人细胞。靶细胞可以是原核细胞或源自原核细胞。靶细胞可以是细菌细胞或可以源自细菌细胞。靶细胞可以是古细菌细胞或源自古细菌细胞。靶细胞可以是真核细胞或源自真核细胞。靶细胞可以是多能干细胞。靶细胞可以是植物细胞或源自植物细胞。靶细胞可以是动物细胞或源自动物细胞。靶细胞可以是无脊椎动物细胞或衍生自无脊椎动物细胞。靶细胞可以是脊椎动物细胞或源自脊椎动物细胞。靶细胞可以是微生物细胞或源自微生物细胞。靶细胞可以是真菌细胞或源自真菌细胞。靶细胞可以来自特定器官或组织。
靶细胞可以是干细胞或祖细胞。靶细胞可包括干细胞(例如,成体干细胞,胚胎干细胞,诱导多能干(iPS)细胞)和祖细胞(例如,心脏祖细胞,神经祖细胞等)。靶细胞可包括哺乳动物干细胞和祖细胞,包括啮齿动物干细胞,啮齿动物祖细胞,人干细胞,人祖细胞等。克隆细胞可包含细胞的后代。靶细胞可包含靶核酸。靶细胞可以在活生物体中。靶细胞可以是遗传修饰的细胞。靶细胞可以是宿主细胞。
靶细胞可以是原代细胞。例如,原代细胞的培养物可以传代0次,1次,2次,4次,5次,10次,15次或更多次。细胞可以是单细胞生物。细胞可以在培养基中生长。
靶细胞可以是患病细胞。患病细胞可具有改变的代谢,基因表达和/或形态学特征。患病细胞可以是癌细胞,糖尿病细胞和凋亡细胞。患病细胞可以是来自患病受试者的细胞。示例性疾病可包括血液病症,癌症,代谢病症,眼病,器官病症,肌肉骨骼病症,心脏病等。
如果靶细胞是原代细胞,则可以通过任何方法从个体收获它们。例如,可通过单采血液成分术,白细胞去除术,密度梯度分离等收获白细胞。可通过活组织检查收获来自组织如皮肤,肌肉,骨髓,脾,肝,胰腺,肺,肠,胃等的细胞。合适的溶液可用于分离或悬浮收获的细胞。这种溶液通常可以是平衡盐溶液(例如生理盐水,磷酸盐缓冲盐水(PBS),Hank's平衡盐溶液等),方便地补充胎牛血清或其他天然存在的因子,以及可接受的缓冲液低浓度。缓冲剂可以包括HEPES,磷酸盐缓冲剂,乳酸盐缓冲剂等。可以立即使用细胞,或者可以将它们储存(例如通过冷冻)。冷冻细胞可以解冻并且能够重复使用。细胞可以在DMSO,血清,培养基缓冲液(例如,10%DMSO,50%血清,40%缓冲培养基)和/或一些其他此类常用溶液中冷冻,用于在冷冻温度下保存细胞。
可以是靶细胞的细胞的非限制性实例包括但不限于淋巴细胞,例如B细胞,T细胞(细胞毒性T细胞,自然杀伤T细胞,调节性T细胞,T辅助细胞),自然杀伤细胞,细胞因子诱导的杀伤细胞(CIK)细胞(参见例如US20080241194);骨髓细胞,如粒细胞(嗜碱性粒细胞,嗜酸性粒细胞,中性粒细胞/过度中性粒细胞),单核细胞/巨噬细胞,红细胞(网织红细胞),肥大细胞,血小板/巨核细胞,树突细胞;来自内分泌系统的细胞,包括甲状腺(甲状腺上皮细胞,滤泡旁细胞),甲状旁腺(甲状旁腺主细胞,Oxyphil细胞),肾上腺(嗜铬细胞),松果体(松果体细胞)细胞;神经系统细胞,包括神经胶质细胞(星形胶质细胞,小胶质细胞),巨细胞神经分泌细胞,星状细胞,Boettcher细胞和垂体(促性腺激素,皮质激素,甲状腺激素,生长激素,乳酸激素);呼吸系统细胞,包括肺细胞(I型肺细胞,II型肺细胞),Clara细胞,杯状细胞,尘埃细胞;循环系统的细胞,包括心肌细胞,周细胞;消化系统的细胞,包括胃(胃主细胞,壁细胞),杯状细胞,潘氏细胞,G细胞,D细胞,ECL细胞,I细胞,K细胞,S细胞;肠内分泌细胞,包括肠嗜铬细胞,APUD细胞,肝脏(肝细胞,库普弗细胞),软骨/骨/肌肉;骨细胞,包括成骨细胞,骨细胞,破骨细胞,牙齿(成骨细胞,成釉细胞);软骨细胞,包括软骨细胞,软骨细胞;皮肤细胞,包括毛细胞,角质形成细胞,黑素细胞(痣细胞);肌细胞,包括肌细胞;泌尿系统细胞,包括足细胞,肾小球旁细胞,肾小球系膜细胞/肾小球系膜细胞,肾近端小管刷状缘细胞,黄斑细胞;生殖系统细胞,包括精子,支持细胞,Leydig细胞,卵子;和其他细胞,包括脂肪细胞,成纤维细胞,肌腱细胞,表皮角质形成细胞(分化表皮细胞),表皮基底细胞(干细胞),指甲和脚趾 甲角质形成细胞,指甲基底细胞(干细胞),髓质毛细胞,皮质毛轴细胞,角质毛干细胞,角质毛根鞘细胞,Huxley层发根鞘细胞,Henle层毛根鞘细胞,外毛鞘细胞,毛发基质细胞(干细胞),湿层状屏障上皮细胞,角膜,舌,口腔,食道,肛管,远端尿道和阴道的复层鳞状上皮表面上皮细胞,角膜上皮,舌,口腔,食道,肛管,远端尿道和阴道的基底细胞(干细胞),尿上皮细胞(排尿膀胱和尿管),外分泌分泌上皮细胞,唾液腺粘液细胞(富含多糖的分泌物),唾液腺浆液细胞(富含糖蛋白酶的分泌),舌中的Von Ebner腺体细胞(洗涤味蕾),乳腺细胞(乳汁分泌),泪腺细胞(泪液分泌),耳中的胭脂腺细胞(蜡分泌物),外泌汗腺黑暗细胞(糖蛋白分泌),Eccrine汗腺透明细胞(小分子分泌),大汗腺汗腺细胞(气味分泌物,性激素敏感),眼睑Moll细胞腺体(专门的汗腺),皮脂腺细胞(富含脂质的皮脂分泌物),鼻子中的Bowman腺体细胞(清洗嗅上皮),Brunner腺体十二指肠中的细胞(酶和碱性粘液),精囊细胞(分泌精液成分,包括用于游泳精子的果糖),前列腺细胞(分泌精液成分),Bulbourethral腺细胞(粘液分泌),前庭大腺细胞(阴道润滑剂)分泌),Littre细胞腺体(粘液分泌),子宫内膜细胞(碳水化合物分泌),呼吸和消化道分离的杯状细胞(粘液分泌),胃粘膜细胞(粘液分泌),胃腺发酵细胞(胃蛋白酶原分泌),胃腺泌酸细胞(盐酸分泌),胰腺腺泡细胞(碳酸氢盐和消化酶分泌),小肠Paneth细胞(溶菌酶分泌),II型肺肺细胞(表面活性物质分泌),肺Clara细胞,激素分泌细胞,垂体前叶细胞,Somatotropes,Lactotropes,Thyrotropes,Gonadotropes,Corticotropes,中间垂体细胞,Magnocellular神经分泌细胞,肠道和呼吸道细胞,甲状腺细胞,甲状腺上皮细胞,滤泡旁细胞,甲状旁腺细胞,甲状旁腺主细胞,Oxyphil细胞,肾上腺细胞,嗜铬细胞,睾丸Ley挖细胞,卵巢卵泡内膜细胞,破裂卵巢卵泡黄体细胞,颗粒细胞叶黄素细胞,Theca叶黄素细胞,Juxtaglomerular细胞(肾素分泌),肾脏Macula densa细胞,代谢和储存细胞,,屏障功能细胞(肺,肠,外分泌腺和泌尿生殖道),肾,I型肺细胞(肺内衬空气间隙),胰腺导管细胞(中心细胞),非环状导管细胞(汗腺,唾液腺,乳腺等),导管细胞(精囊,前列腺等),衬里封闭体内腔的上皮细胞,具有推进功能的纤毛细胞,细胞外基质分泌细胞,收缩细胞;骨骼肌细胞,干细胞,心肌细胞,血液和免疫系统细胞,红细胞(红细胞),巨核细胞(血小板前体),单核细胞,结缔组织巨噬细胞(各种类型),表皮朗格汉斯细胞,破骨细胞(骨中),树突状细胞(淋巴组织),小胶质细胞(中枢神经系统),中性粒细胞,嗜酸性粒细胞,嗜碱性粒细胞,肥大细胞,辅助T细胞,抑制性T细胞,细胞毒性T细胞,自然杀伤T细胞,B细胞,天然杀伤细胞,网织红细胞,干细胞和定向祖细胞用于血液和免疫系统(各种类型),多能干细胞,Totipotent干细胞,诱导多能干细胞,成体干细胞,感觉传感器细胞,自主神经细胞,感觉器官和外周神经元支持细胞,中枢神经系统神经元和神经胶质细胞,晶状体细胞,色素细胞,黑素细胞,视网膜色 素上皮细胞,生殖细胞,Oogonium/Oocyte,Spermatid,Spermatocyte,S permatogonium细胞(精母细胞的干细胞),精子,护士细胞,卵巢滤泡细胞,支持细胞(睾丸),胸腺上皮细胞,间质细胞和间质肾细胞,或经过加工改造或照射的非人体细胞如K562、NK92等。靶细胞可以是天然细胞,也可以是经过修饰的细胞。
特别感兴趣的是癌细胞。在一些实施方案中,靶细胞是癌细胞。癌细胞的非限制性实例包括癌细胞,包括棘皮瘤,Acinic细胞癌,听神经瘤,Acral lentiginous黑素瘤,Acrospiroma,急性嗜酸细胞白血病,急性淋巴细胞白血病,急性巨核细胞白血病,急性单核细胞白血病,成熟的急性成髓细胞白血病,急性骨髓性树突状细胞白血病,急性髓细胞白血病,急性早幼粒细胞白血病,金刚病,腺癌,腺样囊性癌,腺瘤,腺瘤样牙源性肿瘤,肾上腺皮质癌,成人T细胞白血病,侵袭性NK细胞白血病,艾滋病相关癌症,艾滋病相关淋巴瘤,肺泡软组织肉瘤,成釉细胞瘤,肛门癌,间变性大细胞淋巴瘤,甲状腺未分化癌,血管免疫母细胞性T细胞淋巴瘤,血管平滑肌脂肪瘤,血管肉瘤,附件癌,星形细胞瘤,非典型畸胎瘤性横纹肌样瘤,基底细胞癌,基底样癌,B细胞白血病,B细胞淋巴瘤,Bellini导管癌,Bilia ry tract cancer,膀胱癌,Blastoma,骨癌,骨肿瘤,脑干胶质瘤,脑肿瘤,乳腺癌,Brenner肿瘤,支气管肿瘤,细支气管肺泡癌,棕色肿瘤,伯基特淋巴瘤,未知原发癌,癌类肿瘤,癌,原位癌,阴茎癌,未知原发癌,Carcinosarcoma,Castleman病,中枢神经系统胚胎肿瘤,小脑星形细胞瘤,脑星形细胞瘤,宫颈癌,胆管癌,软骨瘤,软骨肉瘤,脊索瘤,绒毛膜癌,脉络丛乳头状瘤,慢性淋巴细胞白血病,慢性单核细胞白血病,慢性粒细胞白血病,慢性骨髓增生性疾病,慢性中性粒细胞白血病,透明细胞瘤,结肠癌,结肠直肠癌,颅咽管瘤,皮肤T细胞淋巴瘤,德戈斯病,皮肤纤维肉瘤,皮样囊肿,增生性小圆细胞瘤,弥漫性大B细胞淋巴瘤,胚胎发育不良神经上皮细胞肿瘤,胚胎癌,内胚窦瘤,子宫内膜癌,子宫内膜癌,子宫内膜样肿瘤,肠病相关T细胞淋巴瘤,室管膜母细胞瘤,室管膜瘤,上皮样肉瘤,红白血病,食道癌,Esthesioneuroblastoma,Ewing家族肿瘤,Ewing家族肉瘤,尤文氏肉瘤,颅外生殖细胞肿瘤,外生殖细胞肿瘤,肝外胆管癌,乳房外Paget病,输卵管癌,胎儿胎儿,纤维瘤,纤维肉瘤,滤泡性淋巴瘤,滤泡性甲状腺癌,胆囊癌,胆囊癌,神经胶质瘤,神经节细胞瘤,胃癌,胃淋巴瘤,胃肠癌,胃肠道类癌肿瘤,胃肠道间质瘤,胃肠道间质瘤,生殖细胞肿瘤,生殖细胞瘤,妊娠绒毛膜癌,妊娠滋养细胞肿瘤,骨巨细胞瘤,多形性胶质母细胞瘤,胶质瘤,脑胶质瘤病,Glomus肿瘤,Glucagonoma,Gonadoblas toma,Granulosa细胞瘤,毛细胞白血病,毛细胞白血病,头颈癌,头颈癌,心脏癌,血管母细胞瘤,血管外皮细胞瘤,血管肉瘤,心脏癌,血管母细胞瘤,血管外皮细胞瘤,血管肉瘤,血液系统恶性肿瘤,肝细胞癌,肝脾T细胞淋巴瘤, 遗传性乳腺癌,霍奇金淋巴瘤,霍奇金淋巴瘤,下咽癌,下丘脑神经胶质瘤,炎症性乳腺癌,眼内黑色素瘤,胰岛细胞癌,胰岛细胞瘤,幼年型骨髓细胞白血病,卡波西肉瘤,卡波西氏肉瘤,肾癌,克拉茨金瘤,Krukenberg肿瘤,喉癌,喉癌,恶性黑色素瘤,白血病,白血病,唇腔和口腔癌,脂肪肉瘤,肺癌,黄体瘤,淋巴管瘤,淋巴管肉瘤,淋巴上皮瘤,淋巴细胞白血病,淋巴瘤,巨球蛋白血症,恶性纤维组织细胞瘤,恶性纤维组织细胞瘤,骨恶性纤维组织细胞瘤,恶性胶质瘤,恶性间皮瘤,恶性外周神经鞘瘤,恶性横纹肌样瘤,恶性氚核瘤,MALT淋巴瘤,地幔细胞淋巴瘤a,肥大细胞白血病,纵隔生殖细胞肿瘤,纵隔肿瘤,甲状腺髓样癌,成神经管细胞瘤,成神经管细胞瘤,髓母细胞瘤,黑色素瘤,黑色素瘤,脑膜瘤,Merkel细胞癌,间皮瘤,间皮瘤,转移性鳞状细胞癌,隐匿性原发性,转移性尿路上皮癌,混合苗勒氏肿瘤,单核细胞白血病,口腔癌,粘液瘤,多发性骨髓瘤,多发性骨髓瘤,蕈样真菌病,蕈样真菌病,骨髓增生异常综合征,骨髓增生异常综合征,骨髓性白血病,骨髓瘤,骨髓增生性疾病,粘液瘤,鼻腔癌,鼻咽癌,鼻咽癌,肿瘤,神经瘤,神经母细胞瘤,神经母细胞瘤,神经纤维瘤,神经瘤,结节性黑素瘤,非霍奇金淋巴瘤,非霍奇金淋巴瘤,非黑色素瘤皮肤癌,非小细胞肺癌,眼肿瘤学,寡淋巴细胞瘤,少突神经胶质瘤,嗜酸细胞瘤,视神经鞘膜脑膜瘤,口腔癌,或al癌症,口咽癌,骨肉瘤,骨肉瘤,卵巢癌,卵巢癌,卵巢上皮癌,卵巢生殖细胞肿瘤,卵巢低恶性潜能肿瘤,乳腺Paget病,Pancoast肿瘤,胰腺癌,胰腺癌,乳头状甲状腺癌,乳头瘤病,副神经节瘤,鼻旁窦癌,甲状旁腺癌,阴茎癌,血管周围上皮样细胞瘤,咽癌,嗜铬细胞瘤,中间分化的松果体实质肿瘤,松果体细胞瘤,垂体腺瘤,垂体瘤,浆细胞肿瘤,胸膜肺母细胞瘤,多胚胎瘤,前体T淋巴母细胞淋巴瘤,原发性中枢神经系统淋巴瘤,原发性积液淋巴瘤,原发性肝细胞癌,原发性肝癌,原发性腹膜癌,原始神经外胚层肿瘤,前列腺癌,腹膜假性粘液瘤,直肠癌,肾细胞癌,呼吸道癌,涉及Chromoso上的NUT基因我15,视网膜母细胞瘤,横纹肌瘤,横纹肌肉瘤,里氏转化,骶尾部畸胎瘤,唾液腺癌,肉瘤,神经鞘瘤病,皮脂腺癌,继发性肿瘤,精原细胞瘤,浆液性肿瘤,Sertoli-Leydig细胞瘤,性索间质瘤,Sezary综合征,印戒细胞癌,皮肤癌,小蓝细胞瘤,小细胞癌,小细胞肺癌,小细胞淋巴瘤,小肠癌,软组织肉瘤,生长抑素瘤,烟尘疣,脊髓肿瘤,脊柱肿瘤,脾边缘带淋巴瘤,鳞状细胞癌,胃癌,浅表性扩散黑素瘤,幕上原始神经外胚层肿瘤,表面上皮-间质瘤,滑膜肉瘤,T细胞急性淋巴细胞白血病,T细胞大颗粒淋巴细胞白血病,T细胞白血病,T细胞淋巴瘤,T细胞幼淋巴细胞白血病,畸胎瘤,晚期淋巴癌,睾丸癌,Thecoma,喉癌,胸腺癌,胸腺瘤,Thyroi d癌,肾盂和输尿管移行细胞癌,移行细胞癌,脐尿管癌,尿道癌,泌尿生殖系肿瘤,子宫肉瘤,葡萄膜黑色素瘤,阴道癌,Verner Morrison综合征,疣 状癌,视觉通路胶质瘤,外阴癌,瓦尔登斯特伦巨球蛋白血症,Warthin的肿瘤,Wilms的肿瘤及其组合。在一些实施方案中,靶向癌细胞代表癌细胞群中的亚群,例如癌症干细胞。在一些实施方案中,癌症是造血谱系,例如淋巴瘤。抗原可以是肿瘤相关抗原。
在一些实施方案中,靶细胞形成肿瘤。用本文方法治疗的肿瘤可导致肿瘤生长稳定(例如,一个或多个肿瘤的体积增加不超过1%,5%,10%,15%或20%,和/或不转移)。在一些实施方案中,肿瘤稳定至少约1,2,3,4,5,6,7,8,9,10,11,12或更多周。在一些实施方案中,肿瘤稳定至少约1,2,3,4,5,6,7,8,9,10,11,12或更多个月。在一些实施方案中,肿瘤稳定至少约1,2,3,4,5,6,7,8,9,10或更多年。在一些实施方案中,肿瘤的大小或肿瘤细胞的数量减少至少约5%,10%,15%,20%,25%,30%,35%,40%,45%,50%,55%,60%,65%,70%,75%,80%,85%,90%,95%或更多。在一些实施方案中,肿瘤被完全消除,或降低至低于检测水平。在一些实施方案中,受试者在治疗后保持无肿瘤(例如缓解)至少约1,2,3,4,5,6,7,8,9,10,11,12或更多周。在一些实施方案中,受试者在治疗后保持无肿瘤至少约1,2,3,4,5,6,7,8,9,10,11,12或更多个月。在一些实施方案中,受试者在治疗后保持无肿瘤至少约1,2,3,4,5,6,7,8,9,10或更多年。
靶细胞的死亡可以通过任何合适的方法确定,包括但不限于在处理之前和之后计数细胞,或测量与活细胞或死细胞(例如活的或死的靶细胞)相关的标记物的水平。细胞死亡程度可通过任何合适的方法确定。在一些实施方案中,相对于起始条件确定细胞死亡程度。例如,个体可具有已知起始量的靶细胞,例如已知大小的起始细胞团或已知浓度的循环靶细胞。在这种情况下,细胞死亡程度可表示为治疗后存活细胞与起始细胞群的比率。在一些实施方案中,细胞死亡程度可通过合适的细胞死亡测定来确定。可以使用各种细胞死亡分析,并且可以使用多种检测方法。检测方法的实例包括但不限于细胞染色,显微术,流式细胞术,细胞分选和这些的组合的使用。
当在治疗期结束后对肿瘤进行手术切除时,可以通过测量坏死(即,死亡)的切除组织的百分比来确定治疗在减小肿瘤大小方面的功效。在一些实施方案中,如果切除组织的坏死百分比大于约20%(例如,至少约30%,40%,50%,60%,70%,80%,90%,则治疗有效)。或100%)。在一些实施方案中,切除组织的坏死百分比是100%,即,没有活肿瘤组织存在或可检测到。
将靶细胞暴露于本文公开的免疫细胞或免疫细胞群可以在体外或体内进行。将靶细胞暴露于免疫细胞或免疫细胞群通常是指使靶细胞与免疫细胞接触和/或足够接近使得靶细胞的抗原或膜蛋白(例如,膜结合或非膜结合)可以与免疫细胞中表达的增强受体或CAR或TCR结合。将靶细胞暴露于免疫细胞或免疫细胞群也通常是指使靶细胞与免疫细 胞接触和/或足够接近使得靶细胞可以与非特异杀伤性免疫细胞结合。通过共培养靶细胞和免疫细胞,可以在体外将免疫细胞或免疫细胞群暴露于靶细胞。靶细胞和免疫细胞可以共培养,例如,作为贴壁细胞或者作为悬浮液。靶细胞和免疫细胞可以在各种合适类型的细胞培养基中共培养,例如与补充物,生长因子,离子等共培养。可以在体内将靶细胞暴露于免疫细胞或免疫细胞群,在一些情况下,通过将免疫细胞施用于受试者(例如人受试者),并允许免疫细胞通过循环系统定位于靶细胞。在一些情况下,可以将免疫细胞递送至靶细胞定位的直接区域,例如通过直接注射。
暴露可以进行任何合适的时间长度,例如至少1分钟,至少5分钟,至少10分钟,至少30分钟,至少1小时,至少2小时,至少3小时,至少4小时,至少5小时,至少6小时,至少7小时,至少8小时,至少12小时,至少16小时,至少20小时,至少24小时,至少2天,至少3天,至少4天,至少5天,至少6天,至少1周,至少2周,至少3周,至少1个月或更长时间。
本文提供的增强受体和CAR的各种结构域可通过化学键连接,例如酰胺键或二硫键;一种小的有机分子(例如烃链);氨基酸序列,例如肽接头(例如,长度约3-200个氨基酸的氨基酸序列),或小的有机分子和肽接头的组合。肽接头可提供所需的灵活性以允许嵌合多肽的所需表达,活性和/或构象定位。肽接头可以具有任何合适的长度以连接至少两个目标结构域,并且优选设计为足够柔韧以允许其连接的一个或两个结构域的正确折叠和/或功能和/或活性。肽接头可具有至少3,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95的长度,或100个氨基酸。在一些实施方案中,肽接头的长度为约0至200个氨基酸,约10至190个氨基酸,约20至180个氨基酸,约30至170个氨基酸,约40至160个氨基酸,约50至150个氨基酸,约60至140个氨基酸,约70至130个氨基酸,约80至120个氨基酸,约90至110个氨基酸。在一些实施方案中,接头序列可包含内源蛋白质序列。在一些实施方案中,接头序列包含甘氨酸,丙氨酸和/或丝氨酸氨基酸残基。在一些实施方案中,接头可含有GS,GGS,GGGGS,GGSG或SGGG的基序,例如多个或重复基序。接头序列可包括任何天然存在的氨基酸,非天然存在的氨基酸或其组合。
可以使用任何合适的递送方法将本公开的组合物和分子(例如,多肽和/或编码多肽的核酸)引入宿主细胞,例如免疫细胞。各种组分可以同时递送或在时间上分开。方法的选择可取决于转化细胞的类型和/或转化发生的环境(例如,体外,离体或体内)。
递送方法可包括使靶多核苷酸接触或将一种或多种核酸引入细胞(或细胞群如免疫细胞)中,所述核酸包含编码本发明组合物的核苷酸序列。包含编码本公开组合物的核苷 酸序列的合适核酸可包括表达载体,其中包含编码本公开内容的一种或多种组合物的核苷酸序列的表达载体是重组表达载体。
递送方法或转化的非限制性实例包括,例如,病毒或噬菌体感染,转染,缀合,原生质体融合,脂质转染,电穿孔,磷酸钙沉淀,聚乙烯亚胺(PEI)介导的转染,DEAE-葡聚糖介导的转染,脂质体介导的转染,粒子枪技术,磷酸钙沉淀,直接微注射和纳米颗粒介导的核酸递送。
在一些方面,本公开提供了包括将一种或多种多核苷酸,或如本文所述的一种或多种载体,或其一种或多种转录物,和/或由其转录的一种或多种蛋白质递送至宿主细胞的方法。在一些方面,本公开内容还提供了由这些方法产生的细胞,以及包含这些细胞或由这些细胞产生的生物(例如动物,植物或真菌)。
常规的基于病毒和非病毒的基因转移方法可用于在哺乳动物细胞或靶组织中引入核酸。此类方法可用于将编码本公开组合物的核酸施用于培养中的细胞或宿主生物中。非病毒载体递送系统可包括DNA质粒,RNA(例如本文所述载体的转录物),裸核酸和与递送载体复合的核酸,例如脂质体。病毒载体递送系统可包括DNA和RNA病毒,其在递送至细胞后可具有附加型或整合的基因组。
非病毒递送核酸的方法可包括脂质转染,核转染,显微注射,生物射弹,病毒体,脂质体,免疫脂质体,聚阳离子或脂质:核酸缀合物,裸DNA,人工病毒粒子和DNA的药剂增强摄取。可以使用适合于多核苷酸的有效受体识别脂质转染的阳离子和中性脂质。递送可以是细胞(例如体外或离体施用)或靶组织(例如体内施用)。可以使用脂质的制备:核酸复合物,包括靶向脂质体,例如免疫脂质复合物。
基于RNA或DNA病毒的系统可用于靶向体内的特定细胞并将病毒有效负载运输至细胞核。病毒载体可以直接(体内)给药,或者它们可以用于体外处理细胞,并且可以任选地(离体)给予修饰的细胞。基于病毒的系统可包括用于基因转移的逆转录病毒,慢病毒,腺病毒,腺相关和单纯疱疹病毒载体。利用逆转录病毒,慢病毒和腺相关病毒基因转移方法可以在宿主基因组中进行整合,这可以导致插入的转基因的长期表达。在许多不同的细胞类型和靶组织中可以观察到高转导效率。
慢病毒可以将其基因组整合进入宿主细胞(如293细胞,或T细胞)。慢病毒可以采用三质粒体系,或四质粒体系。
逆转录病毒的趋向性可以通过掺入外来包膜蛋白来改变,从而扩增靶细胞的潜在靶标群。慢病毒载体是逆转录病毒载体,其可以转导或感染非分裂细胞并产生高病毒滴度。逆转录病毒基因转移系统的选择可取决于靶组织。逆转录病毒载体可包含顺式作用长 末端重复序列,其具有高达6-10kb外源序列的包装能力。最小顺式作用LTR可足以用于载体的复制和包装,其可用于将治疗基因整合到靶细胞中以提供永久性转基因表达。逆转录病毒载体可包括基于鼠白血病病毒(MuLV),长臂猿白血病病毒(GaLV),猿猴免疫缺陷病毒(SIV),人免疫缺陷病毒(HIV)及其组合的载体。
可以使用基于腺病毒的系统。基于腺病毒的系统可以导致转基因的瞬时表达。基于腺病毒的载体可以在细胞中具有高转导效率并且可以不需要细胞分裂。用基于腺病毒的载体可以获得高滴度和表达水平。腺相关病毒(“AAV”)载体可用于用靶核酸转导细胞,例如,在体外产生核酸和肽,以及用于体内和离体基因治疗程序。
包装细胞可用于形成能够感染宿主细胞的病毒颗粒。此类细胞可包括293细胞(例如,用于包装慢病毒或腺病毒)和Psi2细胞或PA317细胞(例如,用于包装逆转录病毒)。可以通过产生将核酸载体包装到病毒颗粒中的细胞系来产生病毒载体。载体可含有包装和随后整合到宿主中所需的最小病毒序列。载体可含有其他病毒序列,其被待表达的多核苷酸的表达盒取代。缺失的病毒功能可以通过包装细胞系反式提供。例如,AAV载体可以包含来自AAV基因组的ITR序列,其是包装和整合到宿主基因组中所必需的。病毒DNA可以包装在细胞系中,该细胞系可以含有编码其他AAV基因的辅助质粒,即rep和cap,而缺少ITR序列。细胞系也可以用腺病毒作为辅助细胞感染。辅助病毒可以促进AAV载体的复制和来自辅助质粒的AAV基因的表达。腺病毒的污染可以通过例如腺病毒比AAV更敏感的热处理来减少。可以使用用于将核酸递送至细胞的其他方法,例如,如US20030087817中所述,其通过引用并入本文。
可以用本文所述的一种或多种载体瞬时或非瞬时转染宿主细胞。可以转染细胞,因为它在受试者中天然存在。细胞可以取自或来自受试者并转染。细胞可以源自取自受试者的细胞,例如细胞系。在一些实施方案中,用本文所述的一种或多种载体转染的细胞用于建立包含一种或多种载体衍生序列的新细胞系。在一些实施方案中,使用用本公开的组合物瞬时转染的细胞(例如通过瞬时转染一种或多种载体,或用RNA转染)用于建立包含含有修饰但缺乏任何其他外源序列的细胞的新细胞系。
与宿主细胞相容的任何合适的载体可以与本公开的方法一起使用。用于真核宿主细胞的载体的非限制性实例包括pXT1,pSG5(StratageneTM),pSVK3,pBPV,pMSG和pSVLSV40(PharmaciaTM)。
使细胞与组合物接触可以在任何培养基中和在促进细胞存活的任何培养条件下发生。例如,可以将细胞悬浮在任何方便的适当营养培养基中,例如Iscove改良的DMEM或RPMI 1640,补充有胎牛血清或热灭活的山羊血清(约5-10%),L-谷氨酰胺,硫醇,特别 是2-巯基乙醇和抗生素,例如青霉素和链霉素。培养物可含有细胞响应的生长因子。如本文所定义的生长因子是能够通过对跨膜受体的特异性作用促进细胞在培养物或完整组织中的存活,生长和/或分化的分子。生长因子可包括多肽和非多肽因子。
在许多实施方案中,所选择的递送系统靶向特定组织或细胞类型。在一些情况下,通过将递送系统与组织或细胞特异性标记物(例如细胞表面蛋白质)结合来实现递送系统的组织或细胞靶向。可以定制病毒和非病毒递送系统以靶向感兴趣的组织或细胞类型。
可以施用含有本文所述的分子(例如,多肽和/或编码多肽的核酸或蛋白)或免疫细胞的药物组合物用于预防性和/或治疗性治疗。在治疗应用中,组合物可以施用于已经患有疾病或病症的受试者,其量足以治愈或至少部分地阻止疾病或病症的症状,或治愈,愈合,改善或改善条件。对该用途有效的量可以根据疾病或病症的严重程度和病程,先前的治疗,受试者的健康状况,体重和对药物的反应以及治疗医师的判断而变化。
多种治疗剂可以以任何顺序或同时施用。如果同时,多种治疗剂可以以单一,统一的形式或以多种形式提供,例如,作为多个单独的药丸或细胞溶液。分子或细胞溶液可以在单个包装中或在多个包装中一起或分开包装。一种或所有治疗剂可以多剂量给予。如果不同时,多次剂量之间的时间可以变化到大约1~24个月。
本文所述的分子或细胞可以在疾病或病症发生之前,期间或之后施用,并且施用含有化合物的组合物的时间可以变化。例如,药物组合物可以用作预防剂,并且可以连续给予具有病症或疾病倾向的受试者,以便预防疾病或病症的发生。分子、细胞和药物组合物可以在症状发作期间或尽可能快地施用于受试者。分子的给药可以在症状发作的最初48小时内,在症状发作的前24小时内,在症状发作的前6小时内,或在症状发作的3小时内开始。初始施用可以通过任何实用的途径,例如通过本文描述的任何途径使用本文描述的任何制剂。可以在检测到或怀疑疾病或病症发作后,在可行的情况下尽快施用分子,并且治疗疾病所需的时间长度,例如,约1个月至约3个月。每个受试者的治疗时间可能不同。
可以将分子包装到生物隔室中。可以将包含该分子的生物隔室施用于受试者。生物隔室可包括但不限于病毒(慢病毒,腺病毒),纳米球,脂质体,量子点,纳米颗粒,微粒,纳米胶囊,囊泡,聚乙二醇颗粒,水凝胶和胶束。
例如,生物隔室可包含脂质体。脂质体可以是包含一个或多个脂质双层的自组装结构,每个脂质双层可以包含两个含有相反取向的两亲脂质分子的单层。两亲性脂质可包含与一个或两个或更多个非极性(疏水)酰基或烷基链共价连接的极性(亲水)头基。疏水性 酰基链与周围水性介质之间的能量上不利的接触诱导两亲性脂质分子自身排列,使得极性头基可朝向双层表面取向,酰基链朝向双层内部取向,有效地屏蔽酰基链不接触与水环境。
在脂质体中使用的可包括磷酸甘油酯和鞘脂,其代表性的例子包括磷脂酰胆碱,磷脂酰乙醇胺,磷脂酰丝氨酸,磷脂酰肌醇,磷脂酸,磷脂酰甘油,棕榈酰油酰磷脂酰胆碱,溶血磷脂酰胆碱,溶血磷脂酰乙醇胺,二肉豆蔻酰基卵磷脂(DMPC),二棕榈酰卵磷脂,优选两亲性化合物的(DPPC实例),二油酰磷脂酰胆碱,二硬脂酰磷脂酰胆碱(DSPC),二亚油酰磷脂酰胆碱和卵鞘磷脂,或其任何组合。
生物隔室可包含纳米颗粒。纳米颗粒的直径可以为约40纳米至约1.5微米,约50纳米至约1.2微米,约60纳米至约1微米,约70纳米至约800纳米,约80纳米。纳米至约600纳米,约90纳米至约400纳米,约100纳米至约200纳米。
在一些情况下,随着纳米颗粒的尺寸增加,释放速率可以减慢或延长,并且随着纳米颗粒的尺寸减小,可以增加释放速率。
纳米颗粒中白蛋白的量可以为约5%至约85%白蛋白(v/v),约10%至约80%,约15%至约80%,约20%至约20%。约70%白蛋白(v/v),约25%至约60%,约30%至约50%,或约35%至约40%。药物组合物可包含最多30,40,50,60,70或80%或更多的纳米颗粒。在一些情况下,本公开的核酸分子可以结合到纳米颗粒的表面。
生物隔室可包含病毒。病毒可以是本公开的药物组合物的递送系统。示例性病毒可包括慢病毒,逆转录病毒,腺病毒,单纯疱疹病毒I或II,细小病毒,网状内皮增生病毒和腺相关病毒(AAV)。可以使用病毒将本公开的药物组合物递送至细胞。病毒可以在体内,离体或体外感染和转导细胞。在离体和体外递送中,可以将转导的细胞施用于需要治疗的受试者。
可以将药物组合物包装到病毒递送系统中。例如,可以通过HSV-1无辅助病毒包装系统将组合物包装到病毒颗粒中。
病毒递送系统(例如,包含本公开的药物组合物的病毒)可以通过直接注射,立体定位注射,脑室内,通过微泵输注系统,通过对流,导管,静脉内,肠胃外,腹膜内和/或皮下注射来施用。注射到需要的受试者的细胞,组织或器官。在一些情况下,细胞可以用病毒递送系统体外或离体转导。转导的细胞可以给予患有疾病的受试者。例如,可以用包含药物组合物的病毒递送系统转导干细胞,并且可以将干细胞植入患者体内以治疗疾病。
在一些情况下,给予受试者的细胞的剂量可为少于1×10
4个细胞/kg,或约1×10
4个细胞/kg,约2×10
4个细胞/kg,约3×10
4细胞/kg,约4×10
4个细胞/kg,约5×10
4个细胞/kg, 约6×10
4个细胞/kg,约7×10
4个细胞/kg,约8×10
4个细胞/kg,约9×10
4个细胞,约1×10
5个细胞/kg,约2×10
5个细胞/kg,约3×10
5细胞/kg,约4×10
5个细胞/kg,约5×10
5个细胞/kg,约6×10
5个细胞/kg,约7×10
5个细胞/kg,约8×10
5个细胞/kg,约9×10
5个细胞,约1×10
6个细胞/kg,约2×10
6个细胞/kg,约3×10
6细胞/kg,约4×10
6个细胞/kg,约5×10
6个细胞/kg,约6×10
6个细胞/kg,约7×10
6个细胞/kg,约8×10
6个细胞/kg,约9×10
6个细胞,约1×10
7个细胞/kg,约5×10
7个细胞/kg,约1×10
8个细胞/kg或更多。这里关于细胞剂量可以按成功转染的有效修饰的细胞数计算,也可以按总细胞数计算。
可以将生物区室通过如下方法引入细胞中,病毒或噬菌体感染,转染,缀合,原生质体融合,脂质转染,电穿孔,磷酸钙沉淀,聚乙烯亚胺(PEI)介导的转染,DEAE-葡聚糖介导的转染,脂质体介导的转染,粒子枪技术,磷酸钙沉淀,直接微注射,纳米颗粒介导的核酸递送等。
在一些实施方案中,施用表达受试者系统的免疫细胞。表达受试者系统的免疫细胞可以在疾病或病症发生之前,期间或之后施用,并且施用免疫细胞的时间可以变化。例如,表达受试者系统的免疫细胞可以用作预防剂,并且可以连续给予具有病症或疾病倾向的受试者,以便预防疾病或病症的发生。免疫细胞可以在症状发作期间或尽可能快地施用于受试者。可以在症状发作的最初48小时内,在症状发作的最初24小时内,在症状发作的最初6小时内,或在症状发作的最初3小时内开始给药。初始施用可以通过任何合适的途径,例如通过本文描述的任何途径使用本文描述的任何制剂。在检测到或怀疑疾病或病症发作后,可以在可行的情况下尽快施用免疫细胞,并且治疗疾病需要一段时间,例如约1个月至约3个月。每个受试者的治疗时间可能不同。
本文所述的分子(例如,多肽和/或核酸)可以以如下范围存在于组合物中,约1mg至约2000mg,约5mg至约1000mg,约10mg至约25mg至500mg,约50mg至约250mg,约100mg至约200mg,约1mg至约50mg,约1mg至约50mg,约50mg至约100mg,约100mg至约150mg,约150mg至约200mg,约200mg至约250mg,约250mg至约300mg,约300mg至约350mg,约350mg至约400mg,约400mg至约450mg,约450mg至约500mg,约500mg至约550mg,约550mg至约600mg,约600mg mg至约650mg,约650mg至约700mg,约700mg至约750mg,约750mg至约800mg,约800mg至约850mg,约850mg至约900mg,约900mg至约950mg,或约950mg至约1000mg。
本文所述的分子(例如,多肽和/或核酸)可以以如下量存在于组合物中,约1mg,约2mg,约3mg,约4mg,约5mg,约10mg,约15mg,约20mg,约25mg,约30mg,约35mg,约40mg,约45mg,约50mg,约55mg,约60mg,约65mg,约70mg,约75mg, 约80mg,约85mg,约90mg,约95mg,约100mg,约125mg,约150mg,约175mg,约200mg,约250mg,约300mg,约350mg,约400mg,约450mg,约500mg,约550mg,约600mg,约650mg,约700mg,约750mg,约800mg,约850mg,约900mg,约950mg,约1000mg,约1050mg,约1100mg,约1150mg,约1200mg,约1250mg,约1300mg,约1350mg,约1400mg,约1450mg,约1500mg,约1550mg,约1600mg,约1650毫克,约1700毫克,约1750毫克,约1800毫克,约1850毫克,约1900毫克,约1950毫克,或约2000毫克。
本文所述的分子(例如,多肽和/或核酸)可存在于每mg提供至少0.1,0.5,1,1.5,2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,10或更多单位活性分子的组合物中。该活性可以是基因表达的调节。在一些实施方案中,递送至受试者的分子的活性单位总数为至少25,000、30,000、35,000、40,000、45,000、50,000、60,000、70,000、80,000、90,000、110,000、120,000、130,000、140,000、150,000、160,000、170,000、180,000、190,000、200,000、210,000、220,000、230,000或250,000或更多单位。在一些实施方案中,递送至受试者的分子的活性单位总数为至多25,000、30,000、35,000、40,000、45,000、50,000、60,000、70,000、80,000、90,000、110,000、120,000、130,000、140,000、150,000、160,000、170,000、180,000、190,000、200,000、210,000、220,000、230,000或250,000或更多单位。
为了更全面地理解和应用本发明,下文将参考实施例和附图详细描述本发明,所述实施例仅是意图举例说明本发明,而不是意图限制本发明的范围。本发明的范围由后附的权利要求具体限定。
实施例1.外周血来源的CAR-T细胞和超级TIL细胞的制备
在实施例1~7中,我们将CD19作为助推抗原,靶向CD19的CAR(使用的CAR的序列参见中国发明申请公开号为CN 110016465A中的SEQ ID NO:1)作为aBA-CAR。
如下制备人CAR-T细胞:采集人PBMC细胞后,以CD3/CD28磁珠激活PBMC来源的CD19
-细胞中的T细胞,转染CD19-CAR慢病毒。
如下制备人超级TIL细胞:从晚期肿瘤患者采集单核细胞后,用磁珠捕获PD1+的T细胞。构建包含如下两个编码序列的慢病毒载体:编码作为aBA-CAR的CD19CAR的核苷酸序列,和编码增强受体——PD1-CD28的核苷酸序列。使用构建的慢病毒转染捕获的PD1+的T细胞。
实施例2.助推佐剂1——自体B细胞助推超级TIL扩增
从患者单采细胞中分离B细胞,并培养到10
7个细胞的数量级。B细胞天然带有CD19膜抗原作为助推抗原。
将如实施例1中所制备的超级TIL细胞分AB两组,各10
6个细胞的数量级,A组使其自然生长作为对照,B组如下处理。将10
6数量级自体B细胞同10
6数量级的超级TIL细胞共培养,10天为一轮,每一轮在体系中增加10
6数量级的自体B细胞,连续培养3轮。可以观察到超级TIL每一轮都比该轮之前扩增了5倍以上,而对照组A组的超级TIL数量未见显著增长。
实施例3.助推佐剂2——自体CD19+T细胞助推超级TIL扩增
从患者单采细胞中分离T细胞,用负载了CD19编码序列的慢病毒转染分离的T细胞,获得CD19+的T细胞作为助推细胞,用CD3/CD28磁珠刺激将该细胞培养至10
7数量级。
将超级TIL细胞分AB两组,各10
6个细胞的数量级,A组使其自然生长作为对照;B组如下处理。将10
6数量级所述自体CD19+T细胞同10
6数量级的超级TIL细胞共培养,10天为一轮,每一轮在体系中增加10
6数量级的自体CD19+T细胞,连续培养3轮。可以观察到超级TIL每一轮都比该轮之前扩增了5倍以上,而对照组A组的超级TIL数量未见显著增长。
实施例4.助推佐剂3——患者自体NK细胞助推超级TIL扩增
从患者单采细胞中分离NK细胞,用负载了CD19编码序列的慢病毒转染分离的NK细胞,获得自体CD19+NK细胞作为助推细胞,用CD3/CD28磁珠刺激将该细胞培养至10
7数量级。
将超级TIL细胞分AB两组,各10
6个细胞的数量级,A组使其自然生长作为对照;B组如下处理。将10
6数量级所述自体CD19+NK细胞同10
6数量级的超级TIL细胞共培养,10天为一轮,每一轮在体系中增加10
6数量级的的所述自体CD19+NK细胞,连续培养3轮。可以观察到超级TIL每一轮都比该轮之前扩增了5倍以上,而对照组A组的超级TIL数量未见显著增长。
实施例5.助推佐剂4——异体B细胞助推超级TIL扩增
将来自不同于受试者的另一位个体志愿者的B细胞培养到10
7数量。B细胞天然带有CD19膜抗原作为助推抗原。
将超级TIL细胞分AB两组,各10
6个细胞的数量级,A组使其自然生长作为对照;B组如下处理。将10
6数量级所述异体B细胞同10
6数量级的超级TIL细胞共培养,10天为一轮,每一轮在体系中增加10
6数量级的异体B细胞,连续培养3轮。可以观察到超级TIL每一轮都比该轮之前扩增了5倍以上,而对照组A组的超级TIL数量未见显著增长。
实施例6.助推佐剂5——异体NK细胞助推超级TIL扩增
从不同于受试者的另一位个体志愿者(异体)单采细胞中分离NK细胞,用负载了CD19编码序列的慢病毒转染所述分离的异体NK细胞,获得异体CD19+NK细胞作为助推细胞,培养该细胞至10
7数量级。
将超级TIL细胞分AB两组,各10
6个细胞的数量级,A组使其自然生长作为对照;B组如下处理。将10
6数量级所述异体CD19+NK细胞同10
6数量级的超级TIL细胞共培养,10天为一轮,每一轮在体系中增加10
6数量级的异体CD19+NK细胞,连续培养3轮。可以观察到超级TIL每一轮都比该轮之前扩增了5倍以上,而对照组A组的超级TIL数量未见显著增长。
实施例7.助推佐剂6——携带助推抗原的纳米粒子助推超级TIL扩增
将CD19蛋白附着在纳米粒子上,构建携带助推抗原的纳米粒子。
将超级TIL细胞分AB两组,各10
6个细胞的数量级,A组使其自然生长作为对照;B组如下处理。将负载的CD19蛋白总量合计约为1微克的纳米粒子同10
6数量级的超级TIL细胞共培养,7天为一轮,每一轮在体系中增加负载的CD19蛋白总量合计约为1微克的纳米粒子,连续培养3轮。可以观察到超级TIL每一轮都比该轮之前扩增了5倍以上,而对照组A组的超级TIL数量未见显著增长。
实施例8.二级自体T细胞助推体系,助推超级TIL扩增
用患者自体T细胞构建两种助推细胞,构建二级助推体系。
第一级助推性细胞:用负载了EGFRviii编码序列的慢病毒转染T细胞,获得EGFRviii
+T细胞作为助推细胞,用CD3/CD28磁珠刺激将该细胞培养至10
7数量级。
第二级助推性细胞:用同时负载了CD19编码序列和靶向EGFRviii的CAR的编码序列(编码核苷酸序列如SEQ ID NO:1所示)的慢病毒转染T细胞,得到CD19
+EGFRviii-CAR-T细胞,用CD3/CD28磁珠刺激培养该细胞至10
7数量级。
将超级TIL细胞分ABC三组,各10
6个细胞的数量级,A组使其自然生长作为对照;B组和C组如下处理。
在B组中,将10
6数量级的第二级助推性细胞(
CD19
+EGFRviii-CAR-T细胞)与超级TIL共培养,作为使用单级助推细胞的阳性对照。即将10
6数量级的二级助推细胞同10
6数量级的超级TIL细胞共培养,10天为一轮,每一轮在体系中增加10
6的二级助推细胞,连续培养3轮。
在C组中,将第一级助推细胞(EGFRviii
+T细胞)与第二级助推细胞(CD19
+EGFRviii-CAR-T细胞)共培养10天之后,加入10
6数量级的超级TIL细胞,同时再加入10
6数量级的第一级助推细胞,将超级TIL在此环境中共培养,10天为一轮,每10天加入10
6数量级的第一级助推细胞,共培养三轮。
可以观察到B组的超级TIL每一轮都比该轮之前扩增了5倍以上,而C组每一轮扩增的倍数比B组要更多。而A组超级TIL数量未见显著增长。
实施例9.异体NK+自体T细胞的二级助推体系,助推超级TIL扩增
用异体NK细胞和患者自体T细胞构建两种助推细胞,构建二级助推体系。
第一级助推性细胞:用负载了EGFRviii编码序列的慢病毒转染异体NK细胞,获得EGFRviii
+NK细胞作为助推细胞,用CD3/CD28磁珠刺激培养该细胞至10
7数量级。
第二级助推性细胞:用同时负载了CD19编码序列和靶向EGFRviii的CAR的编码序列(SEQ ID NO:1)的慢病毒转染自体T细胞,得到CD19
+EGFRviii-CAR-T细胞,用CD3/CD28磁珠刺激将该细胞培养至10
7数量级。
将超级TIL细胞分ABC三组,各10
6数量级,A组使其自然生长作为对照。
B组如下处理:将10
6数量级的第二级助推性细胞(CD19
+EGFRviii-CAR-T细胞)与超级TIL共培养,作为使用单级助推细胞的阳性对照。即将10
6数量级的二级助推细胞同10
6数量级的超级TIL细胞共培养,10天为一轮,每一轮在体系中增加10
6数量级的二级助推细胞,连续培养3轮。
C组如下处理:将第一级助推细胞(EGFRviii
+NK细胞)与第二级助推细胞(CD19
+EGFRviii-CAR-T细胞)共培养10天之后,加入10
6数量级的超级TIL细胞,同时再 加入10
6数量级的第一级助推细胞,将超级TIL在此环境中共培养,10天为一轮,每10天加入10
6数量级的第一级助推细胞,共培养三轮。
可以观察到B组超级TIL每一轮都比该轮之前扩增了5倍以上,而C组每一轮扩增的倍数比B组要更多。而A组超级TIL数量未见显著增长。
实施例10.比较B细胞及两种助推抗原为CD19-CD86的人工助推细胞助推CAR-T细胞
扩增的效应
本实施例比较了三种助推细胞对特定免疫细胞——靶向CD19的CAR-T细胞的助推扩增效应,这三种助推细胞是:1)表达CD19的天然B细胞;2)助推抗原为CD19和CD86的组合并且助推细胞为T细胞的人工助推细胞(缩写为T/CD19-86);和3)助推抗原为CD19和CD86的组合并且助推细胞为K562细胞的人工助推细胞(缩写为K562/CD19-86)。
本实施例的实验流程如下进行。
1.制备PBMC及B细胞
1)从新鲜血液中分离纯化PBMC;
2)通过细胞分选分离CD19+细胞(B细胞)和CD19-细胞。
2.制备靶向CD19的CAR-T细胞(用CART19表示)
1)转染293T细胞,制备包含CD19-CAR cDNA的慢病毒;
2)以CD3/CD28磁珠激活PBMC来源的CD19-细胞中的T细胞;
3)用负载了CD19-CAR的慢病毒转染步骤2)中的T细胞;
4)分析CD19-CAR在转染后的T细胞上的表达。
3.制备助推细胞T/CD19-86
1)转染293T细胞,制备包含CD19-CD86cDNA的慢病毒;
2)以CD3/CD28磁珠激活PBMC来源的CD19-细胞中的T细胞;
3)用负载了CD19-CD86的慢病毒转染步骤2)中T细胞;
4)分析CD19-CD86在转染后的T细胞上的表达。
4.制备助推细胞K562/CD19-86
1)转染293T细胞,制备包含CD19-CD86cDNA的慢病毒;
2)用负载了CD19-CD86的慢病毒转染K562细胞;
3)分析CD19-CD86的表达并分选CD19+CD86+的细胞;
4)扩大培养,100Grayγ-射线照射,分装,冻存。
5.CART19分别与三种助推细胞共培养
1)将CART19均等分为三份,分别与上述2-4中制备的三种助推细胞,即B细胞、T/CD19-CD86、K562/CD19-CD86混合,其中CART19细胞与助推细胞的比例为1:1;
2)调整细胞浓度至1x 10
6/ml,向培养基中补加2U/ml Tscm和100U/mlIL-2(下同);
3)于培养箱中培养细胞,每周一、三半换液(换液后保留一半体积的旧培养基,补加一半新鲜培养基,将细胞浓度维持在1x 10
6/ml);在周五进行流式细胞术分析,根据CART19细胞比例计算并补充加入助推细胞,以保持CART19细胞与助推细胞的比例为1:1,并将培养基全部换为新鲜培养基;
4)第3次加入助推细胞后继续培养一周,使用流式细胞术分析CART19细胞比例。
6.分析数据
计算三种助推细胞分别与CART19共培养之后CART19的扩增倍数,结果如下:
B细胞组,CART19扩增了487倍;
T/CD19-CD86组,CART19扩增了134倍;
K562/CD19-CD86组,CART19扩增了2719倍。
实施例11.比较助推抗原为包含EGFRviii的组合物的人工助推细胞助推两种CAR-T扩增
的效应
本实施例比较了表达包含EGFRviii的组合物的人工助推细胞对两种特定免疫细胞时的助推扩增效应,其中一种免疫细胞包含增强受体。其中,包含EGFRviii的组合物是EGFRviiit(去掉了胞内段的截短的EGFRviii)、CD86、CD137L、mbIL15-IL15Ra的组合物,人工助推细胞是K562,表达该组合物的细胞用K562/EGFRviiit表示。被助推的两种免疫细胞是:1)靶向EGFRviii的CAR-T细胞(用EGFRviii-CAR-T表示);和2)靶向EGFRviii的CAR-T细胞,并增加了PD1-CD28增强受体的修饰(用EGFRviii-ECAR-T表示)。
本实施例的实验流程如下进行。
1.制备PBMC
1)从新鲜血液中分离纯化PBMC;
2)分装,冻存。
2.制备EGFRviii-CART和EGFRviii-ECART
1)转染293T细胞,分别制备包含EGFRviii-CAR和EGFRviii-CAR/PD1-CD28cDNA的慢病毒;
2)复苏PBMC,以CD3/CD28磁珠激活T细胞;
3)分别以制备的三种慢病毒转染CD3/CD28磁珠处理的PBMC;
4)分析EGFRvIII-CAR在T细胞的表达。
3.制备助推细胞K562/EGFRviiit
1)转染293T细胞,制备包含EGFRviiit的组合物的cDNA的慢病毒;
2)用所述慢病毒转染K562细胞;
3)分析EGFRviiit,CD86,CD137L和mbIL15-IL15Ra的表达并分选EGFRviiit+CD86+CD137L+mbIL15+的细胞;
4)扩大培养,100Grayγ-射线照射,分装,冻存。
4.将两种CAR-T与助推细胞K562/EGFRviiit共培养
1)将EGFRviii-CART,EGFRviii-ECART,分别与上述助推细胞K562/EGFRviiit混合,其中CAR+T细胞与助推细胞的比例为1:1;
2)调整细胞浓度至1x 10
6/ml,向培养基中补加30ng/ml IL-21,50U/mlIL-2,10ng/ml IL-15,50ng/ml IL-7(下同);
3)在培养箱中培养细胞,每周一,三半换液(换液后保留一半体积的旧培养基,补加一半新鲜培养基,细胞浓度维持在1x 10
6/ml);在周五进行流式细胞术分析,根据CAR+T细胞比例计算并加入助推细胞,以保持CAR+T细胞与助推细胞的比例为1:1,并将培养基全部换为新鲜培养基;
5)第4次加助推细胞后继续培养一周,使用流式细胞术分析CAR+T细胞比例。
5.分析数据
分析,整理数据,计算助推细胞K562/EGFRviiit分别与EGFRviii-CART和EGFRviii-ECART共培养三周之后,两种CAR-T细胞的扩增倍数,结果如下:
EGFRviii-CART组,CAR-T细胞数量扩增了3.6倍;
EGFRviii-ECART组,CAR-T细胞数量扩增了21.8倍。
Claims (33)
- 一种辅助免疫细胞治疗的佐剂,其特征在于,所述佐剂包含助推抗原(Booster Antigen,BA),所述助推抗原可在体内激活经特定修饰的治疗性免疫细胞,并助推该免疫细胞在体内数量扩增。
- 如权利要求1所述的佐剂,其特征在于,所述助推抗原是外周血细胞或肿瘤细胞或病原体表面的标志物或膜蛋白,所述外周血细胞选自B细胞,T细胞,NK细胞,粒细胞,红细胞,血小板,所述病原体选自HPV病毒,EB病毒,幽门螺旋杆菌(HP),乙肝病毒(HBV),艾滋病毒(HIV)。
- 如权利要求1所述的佐剂,其特征在于,所述助推抗原是一种人类天然蛋白的全部或部分片段的野生型或突变型,或多种人类天然蛋白的全部或部分片段的野生型或突变型的组合物。
- 如权利要求1所述的佐剂,其特征在于,所述助推抗原是CD19或EGFRviii,或是包含CD19和/或CD86和/或CD137L的组合物,或是包含EGFRviii和/或CD86和/或CD137L的组合物。
- 如权利要求1~4中任一项所述的佐剂,其特征在于,所述佐剂选自蛋白、化合物、复合物、助推性细胞或人工纳米材料。
- 如权利要求5所述佐剂,其特征在于,所述助推性细胞是源自受试者自体或异体的外周血单个核细胞(PBMC)或B细胞、T细胞、NK细胞中的一种或多种。
- 如权利要求6所述的佐剂,其特征在于,所述助推性细胞是天然未经修饰的细胞,或是经过修饰的细胞,或是经过永生化改造的B细胞或NK细胞(如NK92)或K562细胞。
- 如权利要求5所述的佐剂,其特征在于,所述佐剂是助推性细胞,其中所述助推抗原跨膜表达在所述助推性细胞上,所述助推抗原是由胞外结合域和跨膜区域组成的融合蛋白,其中所述治疗性免疫细胞可识别所述胞外结合域,所述跨膜区域是所述助推性细胞天然表达的蛋白的部分或全部结构。
- 如权利要求8所述的佐剂,其特征在于,所述助推性细胞是助推性T细胞,所述胞外结合域是EGFRviii或CD19的部分区域,所述跨膜区域是CD3的部分区域。
- 一种能够特异性结合权利要求1~4或6~9中任一项所述助推抗原的嵌合抗原受体(aBA-CAR),其特征在于,所述aBA-CAR包含特异性结合所述助推抗原的抗体的抗原结合结构域。
- 如权利要求10所述的aBA-CAR,其特征在于,包含CD3ζ、靶向所述助推抗原的抗体的可变区和共刺激分子。
- 如权利要求10所述的aBA-CAR,其特征在于,所述共刺激分子选自CD28、41BBz、ICOS中的一种或多种。
- 如权利要求10~12中任一项所述的aBA-CAR,其特征在于,包含CAR或CAR-T细胞表达调控或令CAR-T或CAR-NK细胞自杀或凋亡的开关元件,例如TET-ON。
- 一种治疗性免疫细胞,其特征在于,所述免疫细胞具有双重识别特异性,所述双重识别特异性是对靶细胞的识别特异性以及对权利要求1所述的佐剂中包含的助推抗原的识别特异性,所述靶细胞是对人体有害的细胞如肿瘤细胞,或病毒、细菌、真菌等病原体细胞,由此所述免疫细胞能够由权利要求1所述的佐剂在体内激活并扩增,所述免疫细胞识别靶细胞的靶点和识别助推抗原的靶点是不同的,或是相同的。
- 如权利要求14所述的治疗性免疫细胞,其特征在于,所述免疫细胞表达权利要求10所述的aBA-CAR。
- 如权利要求14或15所述治疗性免疫细胞,其特征在于,所述免疫细胞是T细胞或NK细胞的任意一种或其混合物。
- 如权利要求16所述的治疗性免疫细胞,其特征在于,所述免疫细胞是T细胞。
- 如权利要求17所述的治疗性免疫细胞,其特征在于,所述T细胞是肿瘤识别性T细胞或肿瘤抗原反应性T细胞,其对肿瘤或肿瘤抗原的识别可以是借助天然未经修饰的TCR来识别肿瘤新生抗原(neoantigen)、或肿瘤相关抗原(TAA)、或癌睾抗原、或病毒抗原(如HPV或EBV病毒感染而癌变的细胞表面的病毒抗原),所述肿瘤识别性T细胞或肿瘤抗原反应性T细胞可以经疫苗诱导获得,也可从肿瘤浸润淋巴细胞(TIL)中获得,也可以借助外周血的某些标志物(如PD1、TIM3、CD137、CD39、CD28等)的阳性或阴性筛选而得到。
- 如权利要求17所述的治疗性免疫细胞,其特征在于,所述T细胞是来源于肿瘤浸润T淋巴细胞(TIL),或是经PD1、TIM3、CD137、CD39、CD28等一种或多种标志物阳性或阴性筛选之后的TIL。
- 如权利要求17所述的治疗性免疫细胞,其特征在于,所述T细胞是来源于外周血单核细胞(PBMC),或是来源于经PD1、TIM3、CD137、CD39等一种或多种标志物阳性或阴性筛选之后的PBMC。
- 如权利要求17-20中任一项所述的治疗性免疫细胞,其特征在于,所述T细胞除表达所述aBA-CAR的修饰之外,还经过其他基因修饰。
- 如权利要求17-21中任一项所述的治疗性免疫细胞,其特征在于,所述T细胞是除表达所述aBA-CAR的修饰之外,还经过修饰以表达CAR或外源性TCR的CAR-T或TCR-T细胞,且该CAR或外源性TCR赋予了所述T细胞独立于其天然TCR之外的识别靶细胞的特异性。
- 如权利要求17-22中任一项所述的治疗性免疫细胞,其特征在于,所述T细胞表达增强受体,所述增强受体是跨膜蛋白并由T细胞的胞外结构域(ECD)与细胞内结构域(ICD)组成,所述ECD是所述免疫细胞的靶细胞的膜蛋白的受体、配体、抗体或可与该 膜蛋白结合的其他蛋白结构中的任意一种的完整序列结构或包含其结合域的部分,所述ICD是共刺激信号蛋白如CD28或41BB或ICOS中的任意一种,且不包含CD3。
- 如权利要求23所述的治疗性免疫细胞,其特征在于,所述增强受体的ECD同其配体结合后,会对所述T细胞产生抑制信号,但完整的增强受体同其配体结合后,会对所述T细胞产生激活信号。
- 如权利要求16所述的治疗性免疫细胞,其特征在于,所述免疫细胞是除表达所述aBA-CAR的修饰之外还经过其他基因修饰的NK细胞。
- 如权利要求25所述的治疗性免疫细胞,其特征在于,所述NK细胞是除表达aBA-CAR的修饰之外还经修饰以表达CAR的CAR-NK细胞,且所述CAR使得所述NK细胞特异识别并杀伤靶细胞。
- 如权利要求26所述的治疗性免疫细胞,其特征在于,所述细胞经修饰还包括NKG2D的部分结构。
- 如权利要求1所述的佐剂,其特征在于,该佐剂是由n种如权利要求9所述的助推性细胞组成的级联放大助推体系,其中所述n为正整数,其中第一级助推性细胞表达第一种助推抗原(BA1),第二级助推性细胞表达第二种助推抗原(BA2)和特异性靶向第一种助推抗原的aBA1-CAR,第三级助推性细胞表达第三种助推抗原(BA3)和特异性靶向第二种助推抗原的aBA2-CAR,……第n级助推性细胞表达第n种助推抗原(BAn)和靶向第n-1级助推抗原的aBAn-1-CAR,所述第n种助推抗原BAn可以被所述治疗性免疫细胞所识别,并且各级之间的助推抗原互不相同。
- 如权利要求28所述的佐剂,其特征在于,所述n等于1-10000000范围内的任一正整数。
- 如权利要求28或29所述的佐剂,其特征在于不同级的助推性细胞可以是同一类细胞,或不同类的细胞,或多种细胞的混合物。
- 一种药物组合物,其特征在于,该药物组合物包含如权利要求1-9或28-30中任一项所述的佐剂。
- 一种药物组合,其特征在于,该药物组合包括如权利要求31所述的药物组合物,以及如权利要求14-27中任一项所述的治疗性免疫细胞,其中将所述治疗性免疫细胞与所述药物组合物在恰当时点的单次或连续多次回输,从而使得所述治疗性免疫细胞可被所述药物组合物中的佐剂激活并且在数量上得到扩增,由此可识别并杀伤靶细胞。
- 一种治疗癌症的方法,其特征在于,包括使用权利要求31所述的药物组合物或权利要求32的药物组合,其中将所述药物组合物与所述治疗性免疫细胞与在恰当时点进行单次或连续多次回输。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030087817A1 (en) | 1999-01-12 | 2003-05-08 | Sangamo Biosciences, Inc. | Regulation of endogenous gene expression in cells using zinc finger proteins |
US20080241194A1 (en) | 1998-08-24 | 2008-10-02 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions and methods for protecting organs, tissue and cells from immune system-mediated damage |
CN102586185A (zh) * | 2012-03-12 | 2012-07-18 | 浙江中赢方舟生物工程股份有限公司 | 一种k562细胞扩增激活nk细胞的方法 |
WO2016081518A2 (en) * | 2014-11-17 | 2016-05-26 | Adicet Bio, Inc. | Engineered gamma delta t-cells |
CN105906705A (zh) * | 2016-06-19 | 2016-08-31 | 苏州普罗达生物科技有限公司 | 一种cd19免疫原多肽及其用途 |
WO2016201394A1 (en) * | 2015-06-12 | 2016-12-15 | Miltenyi Biotec Technology, Inc. | Method to treat cancer with engineered t-cells |
WO2017141243A1 (en) * | 2016-02-18 | 2017-08-24 | Enlivex Therapeutics Ltd. | Combination immune therapy and cytokine control therapy for cancer treatment |
CN110016465A (zh) | 2018-01-09 | 2019-07-16 | 北京卡替医疗技术有限公司 | 一种包含b细胞及肿瘤双识别性t细胞的免疫细胞药物 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0859625B1 (en) * | 1995-10-20 | 2008-06-25 | University Of Nebraska Board Of Regents | Composition and methods for enhancing immune responses mediated by antigen-presenting cells |
GB0028319D0 (en) * | 2000-11-20 | 2001-01-03 | Univ Southampton | Materials and methods relating to fusion proteins for inducing an immune response |
EP2948544A4 (en) * | 2013-01-28 | 2016-08-03 | St Jude Childrens Res Hospital | CHIMERIC RECEPTOR WITH NKG2D SPECIFICITY FOR CELL THERAPY AGAINST CANCER AND INFECTION DISEASES |
AU2015339402B2 (en) * | 2014-10-27 | 2021-08-26 | Fred Hutchinson Cancer Center | Compositions and methods for boosting the efficacy of adoptive cellular immunotherapy |
AU2015343013B2 (en) * | 2014-11-05 | 2020-07-16 | Board Of Regents, The University Of Texas System | Gene modified immune effector cells and engineered cells for expansion of immune effector cells |
AR105433A1 (es) * | 2015-07-21 | 2017-10-04 | Novartis Ag | Métodos para mejorar la eficacia y expansión de las células inmunes |
WO2018075794A1 (en) * | 2016-10-19 | 2018-04-26 | City Of Hope | Use of triplex cmv vaccine in car t cell therapy |
WO2018111340A1 (en) * | 2016-12-16 | 2018-06-21 | Novartis Ag | Methods for determining potency and proliferative function of chimeric antigen receptor (car)-t cells |
JP7337773B2 (ja) * | 2017-07-29 | 2023-09-04 | ジュノー セラピューティクス インコーポレイテッド | 組換え受容体を発現している細胞を増大させるための試薬 |
-
2019
- 2019-02-11 CN CN201910106097.7A patent/CN111544585A/zh active Pending
-
2020
- 2020-02-11 EP EP20755525.1A patent/EP3926042A4/en active Pending
- 2020-02-11 CN CN202080013608.1A patent/CN113811602A/zh active Pending
- 2020-02-11 JP JP2021546810A patent/JP2022520777A/ja active Pending
- 2020-02-11 WO PCT/CN2020/074686 patent/WO2020164465A1/zh unknown
- 2020-02-11 US US17/429,835 patent/US20220233589A1/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080241194A1 (en) | 1998-08-24 | 2008-10-02 | The Board Of Trustees Of The Leland Stanford Junior University | Compositions and methods for protecting organs, tissue and cells from immune system-mediated damage |
US20030087817A1 (en) | 1999-01-12 | 2003-05-08 | Sangamo Biosciences, Inc. | Regulation of endogenous gene expression in cells using zinc finger proteins |
CN102586185A (zh) * | 2012-03-12 | 2012-07-18 | 浙江中赢方舟生物工程股份有限公司 | 一种k562细胞扩增激活nk细胞的方法 |
WO2016081518A2 (en) * | 2014-11-17 | 2016-05-26 | Adicet Bio, Inc. | Engineered gamma delta t-cells |
WO2016201394A1 (en) * | 2015-06-12 | 2016-12-15 | Miltenyi Biotec Technology, Inc. | Method to treat cancer with engineered t-cells |
WO2017141243A1 (en) * | 2016-02-18 | 2017-08-24 | Enlivex Therapeutics Ltd. | Combination immune therapy and cytokine control therapy for cancer treatment |
CN105906705A (zh) * | 2016-06-19 | 2016-08-31 | 苏州普罗达生物科技有限公司 | 一种cd19免疫原多肽及其用途 |
CN110016465A (zh) | 2018-01-09 | 2019-07-16 | 北京卡替医疗技术有限公司 | 一种包含b细胞及肿瘤双识别性t细胞的免疫细胞药物 |
Non-Patent Citations (7)
Title |
---|
"Antibodies, A Laboratory Manual", 1988 |
"Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications", 2010 |
"Current Protocols in Molecular Biology", 1995, ACADEMIC PRESS, article "PCR 2: A Practical Approach" |
RAMOS, C. A. ET AL.: "CAR-T Cell Therapy for Lymphoma", ANNU REV MED., vol. 67, 14 January 2016 (2016-01-14), pages 165 - 183, XP055565230, DOI: 10.1146/annurev-med-051914-021702 * |
SAMBROOKGREEN: "Molecular Cloning: A Laboratory Manual", 2012 |
See also references of EP3926042A4 |
TRAN E ET AL.: "Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer", SCIENCE, vol. 344, 2014, pages 641 - 644 |
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