CN112143707A - Immune cell for treating autoimmune cell and application thereof - Google Patents
Immune cell for treating autoimmune cell and application thereof Download PDFInfo
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- CN112143707A CN112143707A CN202011048134.2A CN202011048134A CN112143707A CN 112143707 A CN112143707 A CN 112143707A CN 202011048134 A CN202011048134 A CN 202011048134A CN 112143707 A CN112143707 A CN 112143707A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/7051—T-cell receptor (TcR)-CD3 complex
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
Abstract
The invention relates to the technical field of biological cells, in particular to an immune cell expressing a chimeric antigen receptor, and specifically relates to an immune cell for treating autoimmune cells and application thereof. An immune cell for treating an autoimmune cell, said immune cell expressing a chimeric antigen receptor. The immune cells of the invention express a CAR that specifically recognizes the idiotype of the anti-autoantibody; in addition, the immune cell can specifically kill B cells secreting anti-autoantibodies; and the killing effect is accurate, the safety is higher, the recurrence is not easy, and the life quality of the patient is improved.
Description
Technical Field
The invention relates to the technical field of biological cells, in particular to an immune cell expressing a chimeric antigen receptor, and specifically relates to an immune cell for treating autoimmune cells and application thereof.
Background
In recent years, tumor immunotherapy has been rapidly developed, especially Adoptive Cell Therapy (ACT), which refers to a method of isolating immune cells such as T cells and NK cells from a patient, amplifying the cells by in vitro modification, and then infusing the cells back into the patient for tumor treatment. In 2013, immunotherapy of tumors was evaluated as the first major breakthrough by Science impurities.
CAR-T and TCR-T are important components of adoptive cell therapy, in particular CAR-T therapy, with significant success in the treatment of hematological tumors, achieving a high remission rate, a typical CAR structure consisting of three parts, scFv, hinge and transmembrane domains, intracellular costimulatory signals and activation domains that recognize tumor antigens extracellularly. The first generation of CARs did not contain intracellular costimulatory signals, and CAR-T cells had lower killing activity and shorter survival time. Thus, second generation CARs began to add costimulatory signals such as CD28 and 4-1BB, and the CAR-T cells with different costimulatory signals also varied in their characteristics, with CD28 enhancing killing activity of CAR-T cells and 4-1BB enhancing killing activity of CAR-T cells while prolonging survival of CAR-T cells. Subsequently, a third generation CAR co-expressing two co-stimulatory signaling domains appeared, however its anti-tumor effect was not as good as the second generation CAR-T. Therefore, the clinical application is now primarily secondary CAR-T cells.
CAR-T therapy achieves remarkable results on the treatment of hematological tumors, the commercialization of the CAR-T therapy is smoothly progressed, and the FDA officially approves two CAR-T drugs to be put on the market in 2017
Autoimmune diseases are diseases in which autoimmune tolerance is broken, and the autoimmune system is activated to attack autoantigens, causing damage to organ tissues. They can be roughly classified into immune diseases caused by T cells and immune diseases caused by B cells. The immune disease caused by B cell is that B cell is stimulated by external, hormone, the latter gene mutation affects the secretion of antibody capable of recognizing self, and the damage of organism tissue and organ is caused, generally anti-DNA antibody, anti-nucleoprotein antibody and the like, the surface of B cell secreting anti-self antibody can express the anti-self antibody.
In recent years, many progress is made in the treatment of autoimmune diseases, but great challenges are still faced, such as easy recurrence, no radical cure, and low quality of life of patients.
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and should not be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
Disclosure of Invention
In view of the above problems, the present invention provides an immune cell for treating autoimmune cells and its application, which utilizes the idiotype of CAR-T targeting anti-autoantibody to specifically kill B cells secreting autoantibody, thereby fundamentally eliminating the source of anti-autoantibody, and has precise targeting and less toxic and side effects. Is expected to further relieve and radically cure the autoimmune diseases.
In order to achieve the purpose, the invention provides the following technical scheme:
an immune cell for treating an autoimmune cell, said immune cell expressing a chimeric antigen receptor.
Preferably, the immune cell is a T cell, NK cell, NKT cell, macrophage, gamma-delta T cell, TIL cell, TCR-T cell or other tumor killing cell.
Preferably, the target of the chimeric antigen receptor is the idiotype of an anti-DNA antibody.
Preferably, the target of the chimeric antigen receptor is one or more of idiotypes 16/6, 32/15, 18/2, 21/28, TOF, AM, F4, NE-1, MIV-7, 4.6.3, PR4, SE7, SA-1, SE10, BEG-2, TH3, 31 and 081.
Preferably, the binding region of the chimeric antigen receptor and the target may be scFv and/or Fab.
Preferably, the expression of the chimeric antigen receptor is a CAR that targets one target, or a CAR that targets two or more targets.
Preferably, the binding region between the chimeric antigen receptor and the target may be a single target, or a bispecific antibody binding to two targets, or 2 or more chimeric antigen receptors may be formed across membranes to recognize different targets.
Preferably, the immune cell gene transfer mode is as follows: lentiviruses, retroviruses, common plasmid vectors, episomal vectors, nano-delivery systems, electrical transduction, transposons, or other delivery systems.
Preferably, the chimeric antigen receptor comprises a leader sequence, a scFv that recognizes a tumor associated antigen, a hinge and transmembrane domain, an intracellular costimulatory domain, and an intracellular activation signal CD3 ζ.
Preferably, the scFv is an scFv of an anti-idiotype antibody; the hinge and transmembrane domains are CD28 or CD8 hinge and transmembrane domains; the intracellular costimulatory domain is CD28 or CD137(4-1BB) or ICOS intracellular costimulatory domain.
The invention also provides a preparation, which comprises the immune cells.
Preferably, the formulation is for use in the prevention and/or treatment of autoimmune diseases.
Preferably, the formulation is a pharmaceutically acceptable carrier, diluent or excipient. Administration of the formulations of the invention may be carried out in any convenient manner, including by spraying, injection, swallowing, infusion, implantation or transplantation.
Compared with the prior art, the invention has the following beneficial effects:
the immune cells of the invention express a CAR that specifically recognizes the idiotype of the anti-autoantibody; in addition, the immune cell can specifically kill B cells secreting anti-autoantibodies; and the killing effect is accurate, the safety is higher, the recurrence is not easy, and the life quality of the patient is improved.
Drawings
FIG. 1 shows the results of flow assays of 16/6 expression in K562-16/6 cells;
FIG. 2 is the structure of 16/6 CAR;
FIG. 3 is an expansion curve of NT cells and 16/6CAR-T cells;
FIG. 4 is the expression of CAR at day 6 of NT cells and 16/6CAR-T cells;
FIG. 5 is the results of in vitro killing of NT cells and 16/6CAR-T cells;
FIG. 6 shows the secretion of IFN-gamma cytokines;
FIG. 7 shows the secretion of IL-2 cytokines;
FIG. 8 shows the in vivo potency of 16/6CAR-T as a test result.
Detailed Description
In the following, the technical solutions of the present invention will be described clearly and completely, and it is obvious that the described embodiments are some, not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Examples
The preparation method and the functional verification of the immune cells comprise the following steps:
step 1: isolation of peripheral blood PBMC and expansion of T cells
Separating mononuclear cells from peripheral blood of a donor, performing density gradient centrifugation using ficol, enriching T cells with a T cell sorting kit (CD3 MicroBeads, human-lymphotized, 130-097-043), activating cultured and expanded T cells using magnetic beads coupled with anti-CD3/anti-CD 28; the Medium was TexMACS GMP Medium (Miltenyi Biotec, 170-.
Step 2: cell line culture
Cell line expressing 16/6 idiotype: k562-16/6, laboratory construction;
cloning a base sequence expressing 16/6 into a PHBVLV lentiviral vector skeleton, placing the PHBV-EF 1 alpha-16/6 under a promoter of EF1 alpha (EF-1 alpha) to form PHBVV-EF 1 alpha-16/6, and transferring three plasmids, namely PHBVV-EF 1 alpha-16/6, a lentiviral envelope Plasmid pMD2.G (Addge, Plasmid #12259) and a lentiviral packaging Plasmid psPAX2(Addge Plasmid #12260) into 293T by using Lipofectamine3000 to prepare a lentiviral complete expression vector; viral supernatants were collected at 48h and 72h, concentrated by ultracentrifugation (Merck Millipore); the concentrated virus can be used for infecting K562, and finally a K562 cell line over-expressing 16/6 is obtained, which is named as K562-16/6, and the detection result of K562-16/6 cell expression 16/6 is shown in figure 1.
As can be seen from FIG. 1, the K562 cell line overexpressing 16/6 expressed 16/6 at 100% and the cell line was successfully constructed.
And step 3: CAR structural design and lentiviral packaging
16/6CAR structure, i.e. 16/6 targeted CAR structure:
the core structure of the CAR includes a secretion signal peptide sequence; scFv of an antibody against anti-16/6; the CD8 transmembrane region; the intracellular segment stimulation signal 4-1BB-CD3 ζ is named 16/6CAR, and the specific structure is shown in FIG. 2;
cloning an expression frame into a PHBV lentiviral vector skeleton, placing the expression frame under a promoter of EF1 alpha (EF-1 alpha) to form PHBVV-EF 1 alpha-16/6 CAR, and transferring three plasmids, namely PHBVV-EF 1 alpha 16/6CAR, a lentiviral envelope Plasmid pMD2.G (Addge, Plasmid #12259) and a lentiviral packaging Plasmid psPAX2(Addge Plasmid #12260) into 293T by using Lipofectamine3000 to prepare a lentiviral complete expression vector; viral supernatants were collected at 48h and 72h, concentrated by ultracentrifugation (Merck Millipore); the concentrated virus is ready for infecting T cells.
And 4, step 4: CAR-T cell preparation
4.1 Lentiviral infection: after the primary T cells which are separated and purified are activated for 1 day, the 2 lentiviruses packaged in the step 3 are used for lentivirus vector infection according to MOI (1-10), and the lentivirus vector is transferred to a cell culture bottle and cultured in a constant temperature incubator at 37 ℃ and 5% CO 2;
4.2 cell proliferation and CAR positivity assay: using lentiviral vectors, CAR-T cells were successfully constructed, designated 16/6CAR T, with T cells not infected with lentivirus as controls (NT);
the number of cells was measured by sampling every day on days 6, 9, 11 and 13, and the results are shown in FIG. 3;
the positive rate of CAR of T cells was measured on day 6, and the results are shown in FIG. 4; the culture medium is subcultured and supplemented every 1-2 days.
As can be seen from figure 3, NT proliferated normally with CAR-T cells, transduced CAR had no significant effect on T cell expansion;
as can be seen from figure 4, CAR-T cells expressed a CAR positive rate of 51%.
And 5: cell killing experiment in vitro
Performing an in vitro killing experiment on the 2T cells obtained in the step 4; the LDH method (promega: G1780) detected the killing effect of CAR-T cells, and the detection results are shown in FIG. 5.
As can be seen from FIG. 5, the killing efficiency is obvious when the target cells and the effector cells are incubated for 6 h.
Step 6: cytokine release assay
And (3) respectively mixing the CAR-T cells obtained in the step (4) with the target cells in a ratio of 1: mixing the target ratio of 1 effect, placing the mixture in an RPMI culture medium, co-culturing for 24h, collecting supernatant, centrifuging the supernatant, taking the supernatant to detect the release level of the cytokines IFN-gamma and IL2, and detecting the release level by using an Elisa kit (abbkine, KET6011 and KET6014), wherein the detection results are shown in FIGS. 6 and 7.
As can be seen from FIGS. 6 and 7, after the CAR-T cells were co-cultured with K562-16/6, the CAR-T cells released a large amount of IFN-. gamma.and IL-2, and after co-cultured with K562, the CAR-T cells secreted only a small amount of IFN-. gamma.and IL-2; indicating that CAR-T can be activated efficiently and specifically by cell surface 16/6 antigen.
And 7: 16/6 in vivo efficacy validation of CAR-T
Taking a NSG mouse with the age of 6-8 weeks, and carrying out vein transplantation on K562-16/6 cells to construct a mouse model; randomized into 4 groups of 5 animals each, high intravenous 16/6CAR-T dose, low intravenous 16/6CAR-T dose, NT, PBS; the survival of the mice, K562-16/6 cell load, was observed on day 0 of injection, and the results are shown in FIG. 8.
As can be seen in FIG. 8, 16/6CAR-T was effective in clearing K562-16/6 cells in the mouse model of NSG.
In conclusion, the immune cells of the invention express CAR, specifically recognize idiotype of anti-autoantibody, and can specifically kill B cells secreting anti-autoantibody; and the killing effect is accurate.
The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teaching. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to enable one skilled in the art to make and use various exemplary embodiments of the invention and various alternatives and modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims and their equivalents.
Claims (13)
1. An immune cell for treating an autoimmune cell, wherein the immune cell expresses a chimeric antigen receptor.
2. The immune cell of claim 1, wherein the immune cell is a T cell, NK cell, NKT cell, macrophage, gamma-delta T cell, TIL cell, TCR-T cell, or other tumor killing cell.
3. The immune cell for treating an autoimmune cell according to claim 1 or 2, wherein the target of the chimeric antigen receptor is the idiotype of an anti-DNA antibody.
4. The immune cell for treating an autoimmune cell according to claim 3, wherein the chimeric antigen receptor targets one or more of idiotypes 16/6, 32/15, 18/2, 21/28, TOF, AM, F4, NE-1, MIV-7, 4.6.3, PR4, SE7, SA-1, SE10, BEG-2, TH3, 31, and 081.
5. The immune cell of claim 3, wherein the binding region of the chimeric antigen receptor and the target is scFv and/or Fab.
6. The immune cell of claim 1, wherein the expression of the chimeric antigen receptor is a CAR that targets one target, or a CAR that targets two or more targets.
7. The immune cell of claim 6, wherein the binding region between the chimeric antigen receptor and the target can be a bispecific antibody that binds to one or two targets, or 2 or more chimeric antigen receptors can be formed across membranes to recognize different targets.
8. The immune cell for treating autoimmune cells according to claim 1, wherein the immune cell is genetically transformed in a manner that: lentiviruses, retroviruses, common plasmid vectors, episomal vectors, nano-delivery systems, electrical transduction, transposons, or other delivery systems.
9. The immune cell of claim 1 or 2, wherein the chimeric antigen receptor comprises a leader sequence, a scFv that recognizes a tumor associated antigen, a hinge and transmembrane domain, an intracellular costimulatory domain, and an intracellular activation signal CD3 ζ.
10. The immune cell of claim 9, wherein the scFv is an anti-idiotypic antibody scFv; the hinge and transmembrane domains are CD28 or CD8 hinge and transmembrane domains; the intracellular costimulatory domain is CD28 or CD137(4-1BB) or ICOS intracellular costimulatory domain.
11. A formulation comprising the immune cell of claim 1.
12. The formulation according to claim 11, wherein the formulation is for use in the prevention and/or treatment of autoimmune diseases.
13. The formulation of claim 11, wherein the formulation is a pharmaceutically acceptable carrier, diluent or excipient.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114369621A (en) * | 2021-12-07 | 2022-04-19 | 深圳市先康达生命科学有限公司 | Gene biological agent and preparation method and application thereof |
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