CN114163534A - Bispecific chimeric antigen receptor of targeted HIV-1 virus envelope protein and preparation method and application thereof - Google Patents
Bispecific chimeric antigen receptor of targeted HIV-1 virus envelope protein and preparation method and application thereof Download PDFInfo
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- CN114163534A CN114163534A CN202111312730.1A CN202111312730A CN114163534A CN 114163534 A CN114163534 A CN 114163534A CN 202111312730 A CN202111312730 A CN 202111312730A CN 114163534 A CN114163534 A CN 114163534A
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- hiv
- chimeric antigen
- antigen receptor
- targeting
- bispecific chimeric
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Abstract
The present invention provides a bispecific chimeric antigen receptor targeting an HIV-1 viral envelope protein, said chimeric antigen receptor comprising: (1) a recognition unit targeting the co-receptor binding site of the HIV-1gp120 protein; (2) recognition units targeting other binding sites of HIV-1gp120 (including but not limited to the CD4 binding site, V1V2 glycan region, V3 glycan region, gp120-gp41 interface or membrane proximal outer region on gp 41); (3) a hinge and transmembrane region and (4) an intracellular signaling domain; optionally, the chimeric antigen receptor further comprises (5) one or more co-stimulatory signaling domains; preferably, the chimeric antigen receptor extracellular recognition domains are in tandem order with the recognition unit targeting the HIV-1gp120 protein co-receptor binding site at the distal membrane end and the recognition unit targeting the other HIV gp120 binding site at the proximal membrane end. The invention provides a brand-new construction method of an HIV-1 virus envelope protein bispecific chimeric antigen receptor, and immune cells modified by the antigen receptor have stronger activation and killing capabilities, can specifically identify and kill HIV-1 infected cells, and have good application prospects.
Description
Technical Field
The invention relates to the technical field of immunotherapy, in particular to a bispecific chimeric antigen receptor of a targeted HIV-1 virus envelope protein and application thereof.
Background
AIDS is an infectious disease which is caused by infection of Human Immunodeficiency Virus type 1 (HIV-1) and threatens the life safety of Human beings, and is one of the most important public health challenges faced by China. Highly effective antiretroviral therapy (HAART) is the first revolution in the history of HIV-1/AIDS treatment, and can effectively control the virus replication level in HIV-1 infected patients, so that the virus load in the peripheral blood of the infected patients is lower than that of a detection line, thereby limiting the progress of AIDS disease. However, HAART still has many non-negligible limitations, such as severe drug toxicity and lifetime limitations. Furthermore, the greatest limitation is the inability to target or clear the HIV-1 virus latent in resting CD4+ T cells in patients. Thus, once HAART treatment is discontinued, viral load levels in the blood of infected individuals will rebound rapidly, which constitutes a major obstacle to cure of HIV-1/AIDS.
How to reactivate latent HIV-1 virus for spontaneous recognition and elimination by the body's immune system is critical in curing AIDS. Also, studies have shown that irreversible immune damage, particularly a reduction in the number and functional exhaustion of cytotoxic T cells, occurs even in infected subjects receiving HAART therapy, suggesting a need for enhancing the clearance of HIV-1 reservoirs by a combination of approaches that enhance the body's HIV-1 specific immune response.
Chimeric antigen receptor (CAR-T cells) are one of the latest technologies in the current adoptive cell therapy technology, and progress from basic immunological mechanism research to clinical immunotherapy application is realized. Among them, CAR-T products CTL019 (norwalk) and KTEC19(Kite) for treating leukemia and lymphoma were approved by the FDA in us in 2017, and brought new eosin for application of immune cell therapy technology. Therefore, genetically modified CAR-T cells are likely to be a favorable weapon for clearing the HIV-1 viral latency pool. Indeed, since the last 90 s, studies of adoptive cell transfer (genetically modified T cells transfer) for the treatment of advanced AIDS patients have begun. In 1994, Roberts et al, selecting the CD4 sequence as the extracellular recognition domain of a CAR, generated T cells expressing the CD4-CD3 zeta chimeric receptor (first generation CAR), and although having the ability to target and kill HIV-1 infected or HIV-1Env expressing cells in vitro, had no success in subsequent phase I and phase II clinical trials. The follow-up of patients in 3 clinical trials by Scholler et al in 2005 revealed that autologous CD4+ and CD8+ T lymphocytes expressing CD4-CD3 zeta CAR could stably survive at least 11 years in HIV-1 infected patients, showing the strong potential of CAR-T in the field of HIV-1 infected cell therapy. The main reasons for the failure of the first generation HIV-1CAR-T cells can be attributed to the following: (1) researchers at the time lacked an understanding of the signaling requirements and co-stimulatory signals for effective T cell function, e.g., improving CAR-T cell performance in vivo by providing a co-stimulatory signal CD28 that is beneficial for cell proliferation, cytokine secretion, and cell survival; (2) the CAR molecule design is inherently deficient, and the direct homing of the CAR extracellular recognition domain to the extracellular domain of CD4 protein may make CAR-T cells the target of HIV-1 attack; (3) transduction using retroviral vectors is inefficient, and in order to obtain sufficient reinfusion of CAR-T cells, excessive in vitro expansion leads to too rapid cell depletion and apoptosis following reinfusion. Kim Anthony-Gonda et al reported a construction method of a bispecific CAR-T cell targeting HIV-1 in an HIV-1 virus targeted multi-specific CAR-T cell study, and the CAR molecule serially connected a mutant CD 4D 1 domain mD1.22, a connecting peptide, a single domain antibody m36.4, a hinge and transmembrane region of CD8, a 4-1BB costimulatory signal domain and a CD3 zeta intracellular signaling domain from N terminal to C terminal. However, through research and comparison, the tandem sequence not only influences the membrane expression level of the CAR molecule, but also obviously weakens the activation capability of CAR-T cells and the killing capability of the CAR-T cells on HIV-1 infected target cells, and is not beneficial to infection control of HIV-1. Thus, there remains a need to further improve and optimize the structural design of bispecific CAR targeting HIV-1, enhancing its control of HIV-1 infection and its ability to clear latent pools
Disclosure of Invention
The technical problem to be solved by the invention is as follows: in order to solve the defects in the prior art, the activation capability of CAR-T cells and the killing capability of target cells infected by HIV-1 are enhanced, the structural design of the bispecific CAR targeting HIV-1 is further improved and optimized, and the control capability of the bispecific CAR on HIV-1 infection and the clearing capability of a latent library are enhanced.
In order to solve the technical problems, the technical scheme provided by the invention is as follows: provided is a bispecific chimeric antigen receptor targeting an HIV-1 viral envelope protein, the bispecific chimeric antigen receptor comprising: a recognition unit targeting the co-receptor binding site of the HIV-1gp120 protein, a linker peptide, a recognition unit targeting other binding sites of HIV-1gp120, a hinge region and transmembrane region, an intracellular signaling domain, one or more co-stimulatory signaling domains; the series sequence of the chimeric antigen receptor extracellular segment is a recognition unit of a targeting HIV-1gp120 protein co-receptor binding site at the far membrane end and a recognition unit of other targeting HIV-1gp120 binding sites at the near membrane end.
The recognition unit targeting the HIV-1gp120 protein co-receptor binding site is a single domain antibody m36.4, 17b or X5.
The connecting peptide is(G4S)nOr Gn。
The recognition units targeting other binding sites of HIV-1gp120 include, but are not limited to, the CD4 binding site, the mutant CD 4D 1 domain, the V1V2 glycan region, the V3 glycan region, the gp120-gp41 interface, or the membrane proximal outer region on gp 41.
The hinge and transmembrane regions are derived from the hinge and transmembrane regions of CD28, CD8 α or CD3 ζ.
The co-stimulatory signaling domain is selected from one or more of CD28, 4-1BB, CD27, ICOS, CD160, CD69, TLR2, CD27, CD40L, CD30, OX40, TIM 1.
The intracellular signaling domain is a CD3 ζ intracellular signaling domain.
Preferably, the bispecific chimeric antigen receptor comprises, in order from N-terminus to C-terminus, a recognition unit targeting the co-receptor binding site of the HIV-1gp120 protein, a linker peptide, a recognition unit targeting other binding sites of HIV-1gp120, a hinge and transmembrane region, one or more costimulatory signal domains, and an intracellular signaling domain.
Preferably, the recognition unit targeting the HIV-1gp120 protein co-receptor binding site is a single-domain antibody m36.4, and the amino acid sequence of the recognition unit is shown as SEQ ID No. 1; the recognition unit targeting other binding sites of HIV-1gp120 is a mutant CD 4D 1 structural domain, and the amino acid sequence of the recognition unit is shown as SEQ ID No. 2.
Preferably, the connecting peptide is 3 XG4S; the hinge region and the transmembrane region are the hinge region and the transmembrane region of CD28, and the amino acid sequence is shown as SEQ ID No. 3; the costimulatory signal domain is the costimulatory signal domain of CD28 and 4-1BB, and the amino acid sequence is shown as SEQ ID No.4 and SEQ ID No. 5; the intracellular signaling structural domain is a CD3 zeta intracellular signaling domain, and the amino acid sequence is shown as SEQ ID No. 6.
Preferably, the chimeric antigen receptor further comprises a signal peptide and a tag, the tag is positioned between the signal peptide and the extracellular recognition domain, the signal peptide is the signal peptide of CD8, and the tag is a Flag tag.
The amino acid sequence of the bispecific chimeric antigen receptor is shown in SEQ ID NO. 7.
The gene nucleotide sequence for coding the bispecific chimeric antigen receptor is shown in SEQ ID NO. 8.
A vector, wherein the vector can express the bispecific chimeric antigen receptor targeting HIV-1 virus envelope protein, and the vector comprises a nucleotide sequence shown in SEQ ID NO. 8. In addition, the invention also provides a genetically engineered T lymphocyte which comprises the vector and can express the bispecific chimeric antigen receptor targeting HIV-1 virus envelope protein.
The preparation method of the genetically engineered T lymphocyte comprises the following steps: connecting the coding sequence of the bispecific chimeric antigen receptor targeting HIV-1 virus envelope protein to a vector, packaging to obtain lentivirus particles, and infecting T lymphocytes with the lentivirus to obtain the bispecific chimeric antigen receptor modified T lymphocytes.
The application of the bispecific chimeric antigen receptor of the targeted HIV-1 virus envelope protein in the preparation of drugs for treating or preventing AIDS.
The invention has the beneficial effects that:
(1) the invention overcomes the defects of the existing design, and simultaneously utilizes the recognition unit targeting the HIV-1gp120 protein co-receptor binding site and the recognition unit targeting other HIV-1gp120 binding sites (including but not limited to CD4 binding site, V1V2 glycan region, V3 glycan region, gp120-gp41 interface or gp41 near membrane end external region) to greatly improve the broad spectrum and specificity of the chimeric antigen receptor for recognizing HIV-1 virus envelope protein, and provides the dominant tandem sequence of the recognition unit targeting the HIV-1gp120 protein co-receptor binding site far away from a cell membrane and the recognition unit targeting other HIV-1gp120 binding sites near the cell membrane.
(2) The invention overcomes the defect of early design of a targeted HIV-1 chimeric antigen receptor, and the cell of the proposed bispecific chimeric antigen receptor contains a costimulatory signal, thereby being beneficial to improving the survival, proliferation and killing capabilities of HIV-1 specific CAR-T cells and increasing the clinical effectiveness.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
figure 1 is a schematic diagram of the M31-CAR bispecific chimeric antigen receptor structure.
Figure 2 is a schematic diagram of the M13-CAR bispecific chimeric antigen receptor structure.
Fig. 3 is a graph of M31CAR and M13CAR expression at the primary T cell membrane surface, where UTD is a T cell control that was not transduced with lentivirus.
FIG. 4 is a graph of M31 CAR-T and M13 CAR-T specifically recognizing the target cell MT4-gp145 and secreting cytokines IFN- γ and IL-2, in which UTD is a lentivirus untransduced T cell control.
FIG. 5 is a graph of the efficiency of M31 CAR-T and M13 CAR-T killing gp145 over-expressing cell lines MT4-gp145, where UTD is a T cell control untransduced with lentivirus.
FIG. 6 is a graph of M31 CAR-T and M13 CAR-T killing gp145 over-expressing cells A549-gp 145.
FIG. 7 is a graph of the efficiency of M31 CAR-T and M13 CAR-T killing reactivated HIV latent cells, where UTD is a non-lentiviral transduced T cell control.
FIG. 8 is a graph of M31 CAR-T susceptibility to HIV-1 virus, in which CD4+The T cell group was a positive control.
Detailed Description
The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.
The experimental procedures of the following examples are, unless otherwise specified, routine in the art. The experimental materials used in the following examples were, unless otherwise specified, purchased from conventional biochemical reagents sales companies, among which:
DMEM medium and RPMI1640 medium were purchased from Corning, and lymphocyte culture medium X-VIVO15 was purchased from Lonza.
The T cell growth medium consists of a basic medium and cytokines, wherein the basic medium is lymphocyte culture medium X-VIVO15, and the cytokines are IL-7 with the final concentration of 5ng/mL, IL-15 with the final concentration of 10ng/mL and IL-21 with the final concentration of 30 ng/mL. Among them, cytokines IL-7 and IL-15 were purchased from R & D, and IL-21 was purchased from near-shore protein science and technology Co.
Fetal bovine serum was purchased from BI corporation.
TurboFect transfection kit was purchased from Thermo Fisher Scientific.
Lenti-X lentivirus concentration reagents were purchased from Takara.
Synthetic genes were purchased from Shanghai Czeri bioengineering, Inc.
Lentiviral expression plasmid pKL was supplied by Conlin Biotechnology (Hangzhou) Inc., and packaging plasmid psPAX2 and envelope plasmid PMD2.G were purchased from Addgene.
Stable 3 chemically competent cells were purchased from shanghai medico biotechnology limited.
The endotoxin-free plasmid miniprep kit and the endotoxin-free plasmid midprep kit were purchased from OMEGA and Macherey Nagel, respectively.
Real-time label-free cell function analyzers (RTCAs) were purchased from shanghai goodpaste biotechnology limited.
EXAMPLE 1 construction of lentivirus expression plasmidsM31CAR and M13CAR genes (shown as SEQ ID No:8 and SEQ ID No:9, respectively) were synthesized by Shanghai Czeri bioengineering, Inc. and cloned into a blank lentiviral expression plasmid (pKL) to obtain pKL-M31-CAR and pKL-M13-CAR recombinant lentiviral expression plasmids, respectively, and the bispecific chimeric antigen receptor structures are shown in FIGS. 1 and 2.
Example 2 packaging, concentration and Titer assay of lentiviruses
1.1 packaging of lentiviruses
HEK293T cell treatment: 24 hours before transfection, HEK293T cells in logarithmic growth phase were collected and seeded in 10cm cell culture dishes (6-8X 10)6Individual cells), cells were grown in complete DMEM medium containing 10mL, placed at 37 ℃, 5% CO2And culturing for 18-24 hours under the condition, and performing transfection when the cell density reaches more than 70-90%.
HEK293T cell transfection: 1mL of basal DMEM medium was added to a 15mL centrifuge tube, and a transfection mixture was prepared for lentiviral expression plasmids (pKL-M31-CAR or pKL-M13-CAR), packaging plasmid psPAX2, envelope plasmid PMD2. G: 1:3:1, in a mass ratio of 15. mu.g of total plasmid per dish. In plasmid amount (μ g): transfection reagent (μ L) ═ 1: 2, adding 30 mu L of TurboFect transfection reagent, incubating at room temperature for 15-20 minutes, adding into a cell culture dish, placing at 37 ℃ and 5% CO2The cells were cultured in a cell incubator for 48 hours and the virus supernatant was collected, centrifuged at 1000 Xg at 4 ℃ for 10 minutes, and the virus supernatant was collected.
1.2 concentration of lentiviruses
And filtering the centrifugally collected virus supernatant by using a 0.45-micron filter, adding a Lenti-X lentivirus concentration reagent with the volume of 1/3 virus supernatant, reversing and uniformly mixing for several times, incubating overnight at 4 ℃, centrifuging for 45 minutes at 2000 Xg and 4 ℃, and obtaining the virus after white precipitate is visible at the bottom of a centrifugal tube. Carefully discard the supernatant, resuspend the white pellet in 1/50-1/100 volumes of blank RPMI1640 medium from the proviral supernatant, split and freeze at-80 ℃ for use.
1.3 lentivirus titer assay Jurkat T cells were assayed at 1X 105One/well was seeded on a 96-well U-plate and the collected lentivirus concentrates were diluted in 10-fold increments. Adding 100 mu L of virus diluent into corresponding holes, adding protamine sulfate serving as an infection promoting reagent, regulating the concentration to 10 mu g/mL, 1000 Xg, carrying out centrifugal infection at 32 ℃ for 90 minutes, after overnight culture, replacing the culture solution, continuing to culture for 48 hours, detecting the proportion of fluorescence positive cells by a flow cytometer, and calculating the virus titer by adopting the following formula: viral titer (TU/mL) 1 × 105X fluorescence positive cell ratio/100 x 1000 x corresponding dilution factor.
Example 3 infection and expansion of T cells
In 48-well flat-bottomed cell culture plates (containing 1X 10)6Pre-activated peripheral blood mononuclear cells), the concentrated lentiviral vectors (LV-M31-CAR and LV-M13-CAR) (MOI 5-10) packaged in example 2 were added, the pro-infective agents protamine sulfate were added at 10 μ g/mL, 1000 × g, and after 90 minutes of centrifugation at 32 ℃, 1 × 10 was added to the well plate6Immunomagnetic beads pre-coated with antibodies to alpha CD 3/alpha CD28 were incubated overnight. The next day, the culture medium was changed to fresh T cell growth medium and the culture continued. Adding fresh T cell growth medium every 2-3 days, and adjusting the cell density to 0.5-2 × 106And (4) cells. And 6-7 days after infection, removing the immunomagnetic beads of the activated T cells, continuing to culture the T cells modified by the amplified bispecific chimeric receptor (M31-CAR or M13-CAR), and detecting the expression condition of the CAR molecules on the surface of the primary cells by using a flow cytometer after the cells rest (6-7 days after the immunomagnetic beads are removed). Results as shown in fig. 3, the expression of M31CAR molecules on the surface of primary cell membranes was significantly better than that of M13CAR, with a positive expression rate of about 5 times that of M13CAR molecules.
Example 4 activation and cytokine secretion of bispecific chimeric antigen receptor expressing T cells
Will be 1 × 105Wild-type MT4 cells or MT4 cells overexpressing gp145 protein (MT4-gp145) were plated in 96-well cell culture U-plates, and non-lentiviral transduced T cells (UTD) or bispecific chimeric antigen receptor expressing (M31 CAR-T or M13 CAR-T) were plated as effector cells: the target cells are 1: a1-ratio was plated in test wells with target cells, 200uL of medium per well. After 24 hours of co-culture, 100uL of the supernatant was collected and assayed for the amounts of the cytokines IFN-. gamma.and IL-2 by ELISA. As shown in FIG. 4, the bispecific chimeric antigen receptor-expressing T cells secreted high levels of the cytokines IFN-. gamma.and IL-2 only when they were co-cultured with MT4-gp145, indicating that the bispecific chimeric antigen receptor-expressing T cells specifically recognized HIV-1 envelope protein and were activated. Comparing cytokine levels of M31CAR and M13CAR expressing T cells, it was found that M31CAR could better mediate activation of modified T cells secreting cytokine levels nearly 2-fold that of M13 CAR.
Example 5 bispecific chimeric antigen receptor expressing T cell killer gp145 overexpressing cell lineCell killing efficiency was measured by two methods, flow cytometry and Real Time unlabeled cell Analysis (RTCA).
Flow cytometry detection: first, MT4-gp145 was labeled with PKH26 dye (1: 1000, water bath at 37 ℃ for 10 minutes). Then 1 × 105The labeled MT4-gp145 cells were plated in 96-well cell culture U-plates with effector cells: target cells ═ 0.4: 1 to the wells containing the target cells were added either non-lentiviral transduced T cells (UTD) or bispecific chimeric antigen receptor expressing (M31 CAR-T or M13 CAR-T) and half of the cells in the wells were aspirated every 24 hours for flow cytometry. The results are shown in figure 5, the T cells expressing bispecific chimeric antigen receptor (M31 CAR-T or M13 CAR-T) can kill MT4-gp145 cells efficiently with a killing efficiency of up to 90% at 48 hours; comparing the killing efficiency of M31 CAR-expressing T cells to M13 CAR-expressing T cells, it was found that M31 CAR-T kills target cells more rapidly with 22.2% higher killing efficiency at 24 hours than M13 CAR-T.
RTCA technology: first, a 16-hole E-Plate electrode Plate was used100 μ L of A549 cells overexpressing gp145 protein (5X 10)4Wells), cell growth was monitored dynamically for 12-15 hours using RTCA. The ratio of effector cells: target cells ═ 1: 1 into wells containing target cells, T cells expressing bispecific chimeric antigen receptors (M31 CAR-T or M13 CAR-T) were added, and the assay results were recorded every 15 minutes for 24 hours.
The results are shown in fig. 6, the T cells expressing bispecific chimeric antigen receptor (M31-CAR or M13-CAR) can rapidly decrease the cell growth curve and effectively kill tumor cells over-expressing gp145 protein, wherein the killing ability of the T cells expressing M31-CAR to target cells is significantly better than that of the T cells expressing M13-CAR, and the killing rate is as high as 92.5% (the killing efficiency of M13 CAR-T cells is 88.3%).
Example 6 killing of a reactivated HIV-1 latent cell line ACH2 by T cells expressing bispecific chimeric antigen receptors
The HIV-1 latent cell line ACH2 was expressed at 1X 106Cells were plated in 6-well plates at a concentration of one cell/mL, activated by adding PMA at a concentration of 10ng/mL to the medium, and harvested after 48 hours of culture. The reactivated ACH2 cell line was stained with PKH26 dye (1: 1000, water bath at 37 ℃ for 10 min). Then 1 × 105Individual labeled ACH2 cells were plated in 96-well cell culture U-plates with effector cells: target cells ═ 0.4: 1 to the wells containing the target cells were added either non-lentiviral transduced T cells (UTD) or bispecific chimeric antigen receptor expressing (M31-CAR or M13-CAR) and half of the cells in the wells were aspirated every 24 hours for flow cytometry. As shown in FIG. 7, T cells expressing bispecific chimeric antigen receptor (M31-CAR or M13-CAR) can kill the HIV-1 latent cell line ACH2, but the killing efficiency between the two is very different; at 48 hours, the killing efficiency of M31-CAR expressing T cells reached 48.33%, 19% higher than M13 CAR-T.
Example 7 bispecific chimeric antigen receptor expressing T cells are not susceptible to HIV-1 Virus
Will CD4+T cells and bispecific chimeric antigen receptor expressing T cells in a 1X 10 ratio6Individual cell/mLPlated at cell culture flat bottom plates at 1: anti-CD 3/CD28 antibody-coated magnetic beads are added at a ratio of 1, and cells are collected after 48-72 hours of activation. Will be 5X 105Activated CD4+T cells or T cells expressing bispecific chimeric antigen receptors were plated in 48-well plates, HIV-1 virus (laboratory adapted strain pNL4-3) was added at an MOI of 0.2 or 2, cultured for 4 days and 8 days, half of the cells in the wells were harvested, fixed and membrane-permeabilized, stained with intracellular p24 protein, and the ratio of p24+ cells was detected by flow assay. As shown in FIG. 8, M31 CAR-T was not susceptible to HIV-1 virus regardless of the multiplicity of infection of 0.2 or 2, and M31 CAR-T was more susceptible to HIV-1 virus than M13 CAR-T.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Sequence listing
<110> university of Compound Dan
<120> bispecific chimeric antigen receptor targeting HIV-1 virus envelope protein, preparation method and application thereof
<160> 9
<170> SIPOSequenceListing 1.0
<210> 2
<211> 117
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Ala Phe Asp Phe Ser Asp Tyr
20 25 30
Glu Met Ser Trp Val Arg Glu Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Asp Ser Gly Asn Thr Ile Tyr Asn Pro Ser Leu Lys
50 55 60
Ser Arg Val Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
65 70 75 80
Gln Met Asn Thr Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala
85 90 95
Ile Tyr Gly Gly Asn Ser Gly Gly Glu Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 2
<211> 99
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 2
Lys Lys Val Val Tyr Gly Lys Lys Gly Asp Thr Val Glu Leu Thr Cys
1 5 10 15
Thr Ala Ser Gln Lys Lys Asn Ile Gln Phe His Trp Lys Asn Ser Asn
20 25 30
Gln Ile Lys Ile Leu Gly Asn Gln Gly Ser Phe Leu Thr Lys Gly Pro
35 40 45
Ser Lys Leu Asn Asp Arg Val Asp Ser Arg Arg Ser Leu Trp Asp Gln
50 55 60
Gly Asn Phe Pro Leu Ile Ile Lys Asn Leu Lys Pro Glu Asp Ser Asp
65 70 75 80
Thr Tyr Ile Cys Glu Val Glu Asp Gln Lys Glu Glu Val Gln Leu Val
85 90 95
Val Val Gly
<210> 3
<211> 66
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 3
Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu Asp Asn Glu Lys Ser Asn
1 5 10 15
Gly Thr Ile Ile His Val Lys Gly Lys His Leu Cys Pro Ser Pro Leu
20 25 30
Phe Pro Gly Pro Ser Lys Pro Phe Trp Val Leu Val Val Val Gly Gly
35 40 45
Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala Phe Ile Ile Phe
50 55 60
Trp Val
65
<210> 4
<211> 41
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 4
Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr
1 5 10 15
Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro
20 25 30
Pro Arg Asp Phe Ala Ala Tyr Arg Ser
35 40
<210> 5
<211> 47
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
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Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe
1 5 10 15
Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly
20 25 30
Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
35 40 45
<210> 6
<211> 113
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 6
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
1 5 10 15
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
20 25 30
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
35 40 45
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
50 55 60
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
65 70 75 80
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
85 90 95
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
100 105 110
Arg
<210> 7
<211> 529
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 7
Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu
1 5 10 15
His Ala Ala Arg Pro Asp Tyr Lys Asp Asp Asp Asp Lys Gln Val Gln
20 25 30
Leu Val Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
35 40 45
Leu Ser Cys Ala Ala Ser Ala Phe Asp Phe Ser Asp Tyr Glu Met Ser
50 55 60
Trp Val Arg Glu Ala Pro Gly Lys Gly Leu Glu Trp Ile Gly Glu Ile
65 70 75 80
Asn Asp Ser Gly Asn Thr Ile Tyr Asn Pro Ser Leu Lys Ser Arg Val
85 90 95
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn
100 105 110
Thr Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Ile Tyr Gly
115 120 125
Gly Asn Ser Gly Gly Glu Tyr Trp Gly Gln Gly Thr Leu Val Thr Val
130 135 140
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
145 150 155 160
Ser Lys Lys Val Val Tyr Gly Lys Lys Gly Asp Thr Val Glu Leu Thr
165 170 175
Cys Thr Ala Ser Gln Lys Lys Asn Ile Gln Phe His Trp Lys Asn Ser
180 185 190
Asn Gln Ile Lys Ile Leu Gly Asn Gln Gly Ser Phe Leu Thr Lys Gly
195 200 205
Pro Ser Lys Leu Asn Asp Arg Val Asp Ser Arg Arg Ser Leu Trp Asp
210 215 220
Gln Gly Asn Phe Pro Leu Ile Ile Lys Asn Leu Lys Pro Glu Asp Ser
225 230 235 240
Asp Thr Tyr Ile Cys Glu Val Glu Asp Gln Lys Glu Glu Val Gln Leu
245 250 255
Val Val Val Gly Ala Ser Ile Glu Val Met Tyr Pro Pro Pro Tyr Leu
260 265 270
Asp Asn Glu Lys Ser Asn Gly Thr Ile Ile His Val Lys Gly Lys His
275 280 285
Leu Cys Pro Ser Pro Leu Phe Pro Gly Pro Ser Lys Pro Phe Trp Val
290 295 300
Leu Val Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr
305 310 315 320
Val Ala Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu
325 330 335
His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg
340 345 350
Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg
355 360 365
Ser Arg Phe Ser Val Val Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile
370 375 380
Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp
385 390 395 400
Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu
405 410 415
Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly
420 425 430
Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr
435 440 445
Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys
450 455 460
Pro Gln Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln
465 470 475 480
Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu
485 490 495
Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr
500 505 510
Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro
515 520 525
Arg
<210> 8
<211> 1587
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 8
atggccctcc cagtgaccgc cctcctgctg ccactcgccc tgctgctgca cgccgccaga 60
cctgattaca aggatgacga cgataagcag gtgcagctgg tgcagtctgg gggaggcttg 120
gtacagcctg gagggtccct gagactctcc tgtgcagcct ctgctttcga tttctctgat 180
tatgaaatga gctgggtccg cgaggctcca gggaaggggc tggagtggat tggggaaatc 240
aatgatagtg gaaacaccat ttacaatccg tccctcaaga gtcgagtcac catctccaga 300
gacaattcca agaacacact gtatctgcaa atgaacaccc tgagagccga ggacacagcc 360
atatattact gtgcgatata tggtggtaac tccgggggag agtactgggg ccagggcacc 420
ctggtcaccg tctcctcagg tggaggcggt tcaggcggag gtggctctgg cggtggcgga 480
tcaaagaagg tggtgtacgg caagaagggc gacaccgtgg agctgacctg caccgccagc 540
cagaagaaga acatccagtt ccactggaag aacagcaacc agatcaagat cctgggcaac 600
cagggcagct tcctgaccaa gggacctagc aagctgaacg acagggttga cagccggcgg 660
agcctgtggg accagggaaa cttcccactg atcatcaaga acctgaagcc agaggacagc 720
gacacctaca tctgcgaggt ggaggaccag aaggaggagg tgcagctggt agtggtaggc 780
gctagcatcg aggtgatgta ccctccccct tacctggaca acgagaagag caacggcacc 840
atcatccacg tgaagggcaa gcacctgtgc cctagccccc tgttccccgg acctagcaag 900
cccttttggg tgctggtggt ggtgggcggc gtgctggcct gttactccct gctggtgacc 960
gtggccttca ttatcttctg ggtgaggagc aagaggagca ggctgctgca cagcgactac 1020
atgaacatga cacccaggag acctggcccc accagaaagc actaccagcc ctatgccccc 1080
cccagagact ttgccgccta cagaagcagg ttcagcgtgg tgaagagggg caggaagaag 1140
ctgctgtaca tcttcaagca gcccttcatg aggcccgtgc agaccaccca ggaggaggac 1200
ggctgcagct gcaggttccc cgaggaggag gaaggcggat gcgagctgag agtgaagttc 1260
tccagaagcg ctgacgcccc tgcctaccag cagggacaga accagctgta taacgagctg 1320
aacctgggca ggagagagga gtacgatgtc ctggacaaga ggagaggacg tgatcctgag 1380
atgggcggca agccccaaag gagaaagaac ccccaggagg gactgtacaa tgagctgcag 1440
aaggacaaga tggccgaggc ctactccgaa atcggcatga aaggcgagag gagaaggggc 1500
aaaggccacg atggcctgta ccagggcctg agcacagcca ccaaagacac atacgacgcc 1560
ctgcacatgc aggccctgcc ccctagg 1587
<210> 9
<211> 1566
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 9
atggccctcc cagtgaccgc cctcctgctg ccactcgccc tgctgctgca cgccgccaga 60
cctaagaagg tggtgtacgg caagaagggc gacaccgtgg agctgacctg caccgccagc 120
cagaagaaga acatccagtt ccactggaag aacagcaacc agatcaagat cctgggcaac 180
cagggcagct tcctgaccaa gggacctagc aagctgaacg acagggttga cagccggcgg 240
agcctgtggg accagggaaa cttcccactg atcatcaaga acctgaagcc agaggacagc 300
gacacctaca tctgcgaggt ggaggaccag aaggaggagg tgcagctggt agtggtaggc 360
ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg gatcacaggt gcagctggtg 420
cagtctgggg gaggcttggt acagcctgga gggtccctga gactctcctg tgcagcctct 480
gctttcgatt tctctgatta tgaaatgagc tgggtccgcg aggctccagg gaaggggctg 540
gagtggattg gggaaatcaa tgatagtgga aacaccattt acaatccgtc cctcaagagt 600
cgagtcacca tctccagaga caattccaag aacacactgt atctgcaaat gaacaccctg 660
agagccgagg acacagccat atattactgt gcgatatatg gtggtaactc cgggggagag 720
tactggggcc agggcaccct ggtcaccgtc tcctcagcta gcatcgaggt gatgtaccct 780
cccccttacc tggacaacga gaagagcaac ggcaccatca tccacgtgaa gggcaagcac 840
ctgtgcccta gccccctgtt ccccggacct agcaagccct tttgggtgct ggtggtggtg 900
ggcggcgtgc tggcctgtta ctccctgctg gtgaccgtgg ccttcattat cttctgggtg 960
aggagcaaga ggagcaggct gctgcacagc gactacatga acatgacacc caggagacct 1020
ggccccacca gaaagcacta ccagccctat gcccccccca gagactttgc cgcctacaga 1080
agcaggttca gcgtggtgaa gaggggcagg aagaagctgc tgtacatctt caagcagccc 1140
ttcatgaggc ccgtgcagac cacccaggag gaggacggct gcagctgcag gttccccgag 1200
gaggaggaag gcggatgcga gctgagagtg aagttctcca gaagcgctga cgcccctgcc 1260
taccagcagg gacagaacca gctgtataac gagctgaacc tgggcaggag agaggagtac 1320
gatgtcctgg acaagaggag aggacgtgat cctgagatgg gcggcaagcc ccaaaggaga 1380
aagaaccccc aggagggact gtacaatgag ctgcagaagg acaagatggc cgaggcctac 1440
tccgaaatcg gcatgaaagg cgagaggaga aggggcaaag gccacgatgg cctgtaccag 1500
ggcctgagca cagccaccaa agacacatac gacgccctgc acatgcaggc cctgccccct 1560
aggtga 1566
Claims (18)
1. A bispecific chimeric antigen receptor targeting an HIV-1 viral envelope protein, comprising: a recognition unit targeting the co-receptor binding site of the HIV-1gp120 protein, a linker peptide, a recognition unit targeting other binding sites of HIV-1gp120, a hinge region and transmembrane region, an intracellular signaling domain, one or more co-stimulatory signaling domains; the series sequence of the chimeric antigen receptor extracellular segment is a recognition unit of a targeting HIV-1gp120 protein co-receptor binding site at the far membrane end and a recognition unit of other targeting HIV-1gp120 binding sites at the near membrane end.
2. The bispecific chimeric antigen receptor targeting the envelope protein of the HIV-1 virus according to claim 1, characterized in that the recognition unit targeting the co-receptor binding site of the HIV-1gp120 protein is the single domain antibody m36.4, 17b or X5.
3. The bispecific chimeric antigen receptor targeting the envelope protein of HIV-1 virus according to claim 1, wherein the linker peptide is（G4S）nOr Gn。
4. The bispecific chimeric antigen receptor targeting the envelope protein of the HIV-1 virus according to claim 1, characterized in that said recognition units targeting other binding sites of HIV-1gp120 include, but are not limited to, the CD4 binding site, the V1V2 glycan region, the V3 glycan region, the gp120-gp41 interface or the membrane proximal outer region on gp 41.
5. The bispecific chimeric antigen receptor targeting the envelope protein of the HIV-1 virus according to claim 1, wherein the hinge and transmembrane regions are derived from the hinge and transmembrane regions of CD28, CD8 α or CD3 ζ.
6. The bispecific chimeric antigen receptor targeting an HIV-1 viral envelope protein according to claim 1, wherein the costimulatory signal domain is selected from one or more of CD28, 4-1BB, CD27, ICOS, CD160, CD69, TLR2, CD27, CD40L, CD30, OX40, TIM 1.
7. The bispecific chimeric antigen receptor targeting an envelope protein of the HIV-1 virus according to claim 1, characterized in that said intracellular signaling domain is the CD3 ζ intracellular signaling domain.
8. The bispecific chimeric antigen receptor targeting an envelope protein of the HIV-1 virus according to claim 1, wherein: the dual specificity chimeric antigen receptor comprises a recognition unit targeting a co-receptor binding site of HIV-1gp120 protein, a connecting peptide, a recognition unit targeting other binding sites of HIV-1gp120, a hinge and transmembrane region, one or more co-stimulatory signal domains and an intracellular signaling domain in sequence from N-terminal to C-terminal.
9. The bispecific chimeric antigen receptor targeting the envelope protein of the HIV-1 virus according to claim 8, wherein the recognition unit targeting the co-receptor binding site of the HIV-1gp120 protein is a single domain antibody m36.4, the amino acid sequence of which is shown in SEQ ID No. 1; the recognition unit targeting other binding sites of HIV-1gp120 is a mutant CD 4D 1 structural domain, and the amino acid sequence of the recognition unit is shown as SEQ ID No. 2.
10. The bispecific chimeric antigen receptor targeting the envelope protein of HIV-1 virus according to claim 8, wherein said linker peptide is 3 XG4S; the hinge region and the transmembrane region are hinges of CD28The region and the transmembrane region, and the amino acid sequence is shown as SEQ ID No. 3; the costimulatory signal domain is the costimulatory signal domain of CD28 and 4-1BB, and the amino acid sequence is shown as SEQ ID No.4 and SEQ ID No. 5; the intracellular signaling structural domain is a CD3 zeta intracellular signaling domain, and the amino acid sequence is shown as SEQ ID No. 6.
11. The bispecific chimeric antigen receptor targeting the envelope protein of HIV-1 virus according to claim 8, further comprising a signal peptide and a tag, wherein the tag is located between the signal peptide and the extracellular recognition domain, and the signal peptide is the signal peptide of CD8 and the tag is a Flag tag.
12. The bispecific chimeric antigen receptor targeting the envelope protein of HIV-1 virus according to claim 8, wherein the amino acid sequence of said bispecific chimeric antigen receptor is represented by SEQ ID No. 7.
13. The bispecific chimeric antigen receptor targeting HIV-1 envelope protein according to claim 8, wherein the nucleotide sequence of the gene encoding said bispecific chimeric antigen receptor is represented by SEQ ID No. 8.
14. A vector capable of expressing the bispecific chimeric antigen receptor targeting the envelope protein of the HIV-1 virus according to claim 1, comprising the nucleotide sequence shown in SEQ ID No. 8.
15. A genetically engineered T lymphocyte, wherein said T lymphocyte
Comprising the vector of claim 14 and capable of expressing a bispecific chimeric antigen receptor targeting an HIV-1 viral envelope protein.
16. A method of producing the genetically engineered T lymphocyte of claim 15, comprising the steps of: connecting the coding sequence of bispecific chimeric antigen receptor targeting HIV-1 virus envelope protein of claim 14 to a vector, packaging to obtain lentiviral particles, and infecting T lymphocytes with the lentivirus to obtain bispecific chimeric antigen receptor modified T lymphocytes.
17. The use of the bispecific chimeric antigen receptor targeting the envelope protein of the HIV-1 virus according to claim 1 for the preparation of a medicament for the treatment or prevention of AIDS.
18. The method for preparing the bispecific chimeric antigen receptor targeting HIV-1 virus envelope protein according to claim 8, which comprises the following steps: nucleotide sequences respectively encoding a recognition unit targeting a co-receptor binding site of HIV-1gp120 protein, a connecting peptide, a recognition unit targeting other binding sites of HIV-1gp120, a hinge and transmembrane region, a co-stimulatory signal region and an intracellular signal transduction structural domain are sequentially connected in series in the 5 'to 3' direction, and are cloned to a blank lentiviral expression vector pKL by using gene synthesis, so that a lentiviral plasmid expressing the bispecific chimeric antigen receptor is obtained.
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| PCT/CN2022/117012 WO2023077943A1 (en) | 2021-11-08 | 2022-09-05 | Bispecific chimeric antigen receptor targeting hiv-1 envelope protein, preparation method therefor and application thereof |
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| WO2023077943A1 (en) * | 2021-11-08 | 2023-05-11 | 复旦大学 | Bispecific chimeric antigen receptor targeting hiv-1 envelope protein, preparation method therefor and application thereof |
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| CN114163534B (en) * | 2021-11-08 | 2023-07-18 | 复旦大学 | Bispecific chimeric antigen receptor targeting HIV-1 virus envelope protein and preparation method and application thereof |
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