WO2020108644A1 - Immunothérapie à car-t combinée basée sur cd19 et cd22 - Google Patents

Immunothérapie à car-t combinée basée sur cd19 et cd22 Download PDF

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WO2020108644A1
WO2020108644A1 PCT/CN2019/122162 CN2019122162W WO2020108644A1 WO 2020108644 A1 WO2020108644 A1 WO 2020108644A1 CN 2019122162 W CN2019122162 W CN 2019122162W WO 2020108644 A1 WO2020108644 A1 WO 2020108644A1
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chimeric antigen
antigen receptor
domain
acid sequence
amino acid
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Junfang Li
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Beijing Meikang Geno Immune Biotechnology Co Ltd
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Beijing Meikang Geno Immune Biotechnology Co Ltd
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Definitions

  • the present application relates to the field of cellular immunotherapy for tumors, in particular to an immune cell mixture comprising an immune cell genetically modified with a chimeric antigen receptor targeting CD19 and an immune cell genetically modified with a chimeric antigen receptor targeting CD22, and an application thereof, and specifically to a method for constructing a chimeric antigen receptor T (CAR-T) cell technology based on tumor specific targets CD19 and CD22 and its application in anti-tumor therapy.
  • CAR-T chimeric antigen receptor T
  • chimeric antigen receptor T cell CAR-T
  • the chimeric antigen receptor typically consists of a tumor-associated antigen-binding region, an extracellular hinge region, a transmembrane region, and an intracellular signaling region.
  • the CAR generally comprises a single chain fragment variable (scFv) region of an antibody or a binding domain specific for a tumor-associated antigen (TAA) , which is coupled to the cytoplasmic domain of a T cell signaling molecule via hinge and transmembrane regions.
  • scFv single chain fragment variable
  • TAA tumor-associated antigen
  • the most common lymphocyte activation moieties include a T cell costimulatory domain in tandem with a T-cell effector function triggering (e.g. CD3 ⁇ ) moiety.
  • the CAR-mediated adoptive immunotherapy allows CAR-transplanted T cells to directly recognize the TAAs on target tumor cells in a non-HLA-restricted manner.
  • B-ALL B cell acute lymphocytic leukemia
  • CLL chronic lymphocytic leukemia
  • One approach to treat these patients is to genetically modify T cells to target the antigens expressed on tumor cells through the expression of CARs.
  • CAR is an antigen receptor designed to recognize cell surface antigens in a human leukocyte antigen (HLA) -independent manner. Attempts in using genetically modified cells expressing CARs to treat these types of patients have achieved promising success.
  • CD19 molecule is a potential target for the treatment of B lymphocyte tumors, and is also a focus in CAR research.
  • the expression of CD19 is restricted to normal and malignant B cells and thus is a widely accepted CAR target for safety tests.
  • T cells genetically modified with a chimeric antigen receptor targeting the CD19 molecule have achieved great success in the treatment of multiple, refractory acute B lymphocytic leukemia, they have significant poor therapeutic effects in the treatment of refractory, recurrent chronic B lymphocytic leukemia and B lymphocyte lymphoma.
  • CN 104788573 A discloses a chimeric antigen receptor hCD19scFv-CD8 ⁇ -CD28-CD3 ⁇ and use thereof.
  • This second-generation chimeric antigen receptor is composed of variable regions of light and heavy chains of anti-human CD19 monoclonal antibody HI19a (hCD19scFv) , a human CD8 ⁇ hinge region, human CD28 transmembrane and intracellular regions, and a human CD3 ⁇ intracellular region in tandem arrangement.
  • hCD19scFv anti-human CD19 monoclonal antibody HI19a
  • a human CD8 ⁇ hinge region a human CD8 ⁇ hinge region
  • human CD28 transmembrane and intracellular regions and a human CD3 ⁇ intracellular region in tandem arrangement.
  • the expression level of CD19 is decreased after a single infusion of CAR-T cells, causing the tumor cells to easily escape immune mechanisms.
  • this second-generation CART causes a strong immune factor storm which has safety concerns.
  • CD19-negative relapse as well as CD19 low-expression B-cell tumors, it is particularly important to combine another potential chimeric antigen receptor to address the problem of easy mutation and low expression of CD19.
  • CD22 is also a potential target for the treatment of malignant B-cell tumors. Like CD19, CD22 is expressed only on the cell surface of B cell lines. According to previous studies on clinical trials using anti-CD22 antibodies, CD22 has been evaluated and confirmed to be a good target for the treatment of B cell malignancies.
  • the present application provides an immune cell mixture comprising an immune cell genetically modified with a chimeric antigen receptor targeting CD19 and an immune cell genetically modified with a chimeric antigen receptor targeting CD22, and an application thereof.
  • the present application initiates combining the two tumor targets, CD19 and CD22, possesses advantages including strong specificity and high targeting ability, and it can effectively improve and prolong the therapeutic effects of CARTs, shows a better therapeutic effect on surface antigens CD19 and CD22-positive leukemia or B-cell lymphoma and can effectively avoid the off-target escape as found in single-targeted therapy.
  • the present application provides an immune cell mixture comprising an immune cell genetically modified with a chimeric antigen receptor targeting CD19 and an immune cell genetically modified with a chimeric antigen receptor targeting CD22.
  • T cells are modified with lentiviral vectors encoding antigen binding domains that bind to tumor surface antigens CD19 and CD22, thus allowing the tumor surface antigens CD19 and CD22 to specifically bind to the chimeric antigen receptors of the present application.
  • CAR-T cells eliminate both tumor cells expressing CD19 and those expressing CD22, effectively avoiding the escape of tumor cells resulting from a low antigen expression, and enhancing the long-term immune effects of CAR-T cells.
  • the two chimeric antigen receptors may be a separate chimeric antigen receptor targeting CD19 and a separate chimeric antigen receptor targeting CD22, respectively.
  • the chimeric antigen receptor targeting CD19 may be combined with the chimeric antigen receptor targeting CD22 to express as a dual chimeric antigen receptor, i.e., the antigen binding domain thereof binds to tumor surface antigens CD19 and CD22. Both cases can achieve a combination therapy of the two chimeric antigen receptors.
  • the chimeric antigen receptor targeting CD19 and the chimeric antigen receptor targeting CD22 each comprises an antigen-binding domain, a transmembrane domain, a costimulatory signaling region, a CD3 ⁇ signaling domain, and an inducible suicide fusion domain in tandem arrangement.
  • the antigen-binding domain is a single chain antibody against tumor surface antigen CD19
  • the antigen-binding domain is a single chain antibody against tumor surface antigen CD22.
  • the chimeric antigen receptor (CAR) of the genetically modified T cell and the single chain antibodies (scFv) of the antigen binding domains for CD19 and CD22 of the genetically modified T cells are exemplified below.
  • the single chain antibody against tumor surface antigen CD19 has an amino acid sequence selected from any one of the group consisting of
  • the amino acid sequence has the activity of a single chain antibody against tumor surface antigen CD19.
  • amino acid sequence (SEQ ID No. 1) of the single-chain antibody against the tumor surface antigen CD19 is listed as follows:
  • the amino acid sequence that shares more than 90%homology or the amino acid sequence that is obtained by modifying, substituting, deleting or adding one or several amino acids can be replaced by other single chain antibodies or humanized CD19 single chain antibodies.
  • the amino acid mutant still functions as a CD19 single-chain antibody.
  • the single chain antibody against the tumor surface antigen CD22 has an amino acid sequence selected from any one of the group consisting of
  • the amino acid sequence has the activity of a single chain antibody against tumor surface antigen CD22.
  • amino acid sequence SEQ ID No. 2 of the single-chain antibody against tumor surface antigen CD22 is listed as follows:
  • the amino acid sequence that shares more than 90%homology or the amino acid sequence that is obtained by modifying, substituting, deleting or adding one or several amino acids can be replaced by other single chain antibodies or humanized CD22 single chain antibodies.
  • the amino acid mutant still functions as a CD22 single-chain antibody.
  • T cells are genetically modified with the chimeric antigen receptor by lentiviral vectors.
  • the CD19-and CD22-based CAR-T cells bind to tumor surface antigens CD19 and CD22, exhibiting a stronger tumor-killing effect.
  • the transmembrane domain is a CD28 transmembrane domain and/or a CD8 ⁇ transmembrane domain.
  • the transmembrane domain can be selected or modified by amino acid substitution.
  • the costimulatory signaling region is any one selected from the group consisting of a CD28 signaling domain, a CD27 signaling domain or a CD137 signaling domain, or a combination of at least two thereof.
  • a person skilled in the art can adjust the arrangement of the CD28 signaling domain, CD27 signaling domain and CD137 signaling domain according to requirements. Different arrangements of the CD28 signaling domain, CD27 signaling domain and CD137 signaling domain will not affect the chimeric antigen receptor.
  • the present application employs the order of CD28-CD27.
  • the fourth-generation CAR comprises an inducible suicide fusion domain which contains a Caspase 9 domain having the amino acid sequence as shown in SEQ ID NO. 3, which is as follows:
  • the inducible suicide fusion domain is connected in tandem with the CD3 ⁇ signaling domain via a 2A sequence.
  • the 2A sequence will cause the protein expressed by the inducible suicide fusion domain to cleave off from the chimeric antigen receptor protein, thereby allowing the chimeric antigen receptor to exert its function.
  • the suicide fusion domain can be activated by injecting an activator, thereby causing the T cells expressing the chimeric antigen receptor to die to lose their functions.
  • the chimeric antigen receptor further comprises a signal peptide which is capable of directing transmembrane transfer of the chimeric antigen receptor.
  • a signal peptide which is capable of directing transmembrane transfer of the chimeric antigen receptor.
  • the signal peptide is a Secretory signal peptide, which is the signal peptide for gene GMCSFR and may have the amino acid sequence as shown in SEQ ID NO. 8, which is as follows: MLLLVTSLLLCELPHPAFLLIP.
  • the Secretory signal peptide is a signal peptide for CD8a gene, and the Secretory signal peptide has the amino acid sequence as shown in SEQ ID NO. 9, which is as follows: MALPVTALLLPLALLLHAARP.
  • the chimeric antigen receptor of the present application may further comprise a hinge region.
  • the hinge region may be selected by those skilled in the art according to actual situation, and is not particularly limited herein. The presence of a hinge region will not affect the performance of the chimeric antigen receptor of the present application.
  • the chimeric antigen receptor targeting CD19 and the chimeric antigen receptor targeting CD22 each comprises a signal peptide, an antigen-binding domain, a transmembrane domain, a costimulatory signaling region, a CD3 ⁇ signaling domain, a 2A sequence and an inducible suicide fusion domain in tandem arrangement.
  • the chimeric antigen receptor is obtained by connecting a Secretory signal peptide, a CD19 antigen-binding domain and/or a CD22 antigen-binding domain, CD8 ⁇ and/or CD28 transmembrane domain (s) , a CD28 extracellular signaling domain, a CD28 intracellular signaling domain, a CD27 intracellular signaling domain, a CD3 ⁇ intracellular signaling domain, a 2A sequence and a FBKP.
  • Casp9 domain in tandem. Specifically, the arrangement is as follows:
  • Casp9 has the amino acid sequence as shown in SEQ ID NO. 4 or an amino acid sequence that shares more than 90%homology therewith.
  • the amino acid sequence as shown in SEQ ID NO. 4 is as follows:
  • Casp9 has the nucleotide sequence as shown in SEQ ID NO. 5 or an nucleotide sequence that shares more than 95%homology therewith.
  • the nucleic acid sequence as shown in SEQ ID NO. 5 is as follows:
  • the chimeric antigen receptor Secretory-CD22 scFv-CD28-CD27-CD3 ⁇ -2A-FBKP has the amino acid sequence as shown in SEQ ID NO. 6 or an amino acid sequence that shares more than 90%homology therewith.
  • the amino acid sequence as shown in SEQ ID NO. 6 is as follows:
  • Casp9 has the nucleotide sequence as shown in SEQ ID NO. 7 or an nucleotide sequence that shares more than 95%homology therewith.
  • the nucleic acid sequence as shown in SEQ ID NO. 7 is as follows:
  • the chimeric antigen receptor further comprises a promoter, which is any one of the group consisting of EF1a, CMV-TAR and CMV, or a combination of at least two thereof.
  • the chimeric antigen receptor is expressed by transducing the nucleic acid encoding the same into T cell.
  • the transduction is performed by transduction into T cells via any one of the group consisting of a viral vector, an eukaryotic expression plasmid and an mRNA sequence, or a combination of at least two thereof, preferably by transduction into T cells via a viral vector.
  • the viral vector is any one of the group consisting of a lentiviral vector and a retroviral vector, or a combination of at least two thereof, preferably a lentiviral vector.
  • the present application provides a recombinant lentivirus mixture comprising a recombinant lentivirus which is obtained by transducing mammalian cells with a viral vector comprising a nucleotide sequence encoding a chimeric antigen receptor targeting CD19 and packaging helper plasmids pNHP and pHEF-VSVG and a recombinant lentivirus which is obtained by transducing mammalian cells with a viral vector comprising a nucleotide sequence encoding a chimeric antigen receptor targeting CD22 and packaging helper plasmids pNHP and pHEF-VSVG.
  • the recombinant lentivirus can efficiently immunize cells including T cells to prepare targeting T cells.
  • the mammalian cell is any one of the group consisting of a 293 cell, a 293T cell and a TE671 cell, or a combination of at least two thereof.
  • the present application provides a pharmaceutical composition comprising the immune cell mixture as described in the first aspect and/or the recombinant lentivirus mixture as described in the second aspect.
  • the present application provides use of the immune cell mixture as described in the first aspect, the recombinant lentivirus mixture as described in the second aspect or the pharmaceutical composition as described in the third aspect for the preparation of chimeric antigen receptor T cells, immune competent cells or tumor therapeutics.
  • the antigen receptor T cells have a good targeting effect and are capable of releasing low dose of immune factors, having a property of low toxic reaction.
  • the tumor is a blood-associated neoplastic disease and/or a solid tumor.
  • the neoplastic disease is selected from, but not limited to, leukemia.
  • the present application provides a method for treating a tumor comprising administrating to a subject in need thereof a therapeutically effective amount of
  • the CD19-and CD22-based CAR-T cells obtained by genetically modifying T cells with the chimeric antigen receptors of the present application bind to tumor surface antigens CD19 and CD22, and kill tumors with a stronger effect, achieving a more significant tumor reduction effect;
  • the two chimeric antigen receptors of the present application specifically recognize tumor surface antigens CD19 and CD22 that are highly expressed in leukemia and lymphoma and has a safer and more significant effect than other chimeric antigen receptors and other tumor antigens, thereby improving the immune effects of CAR-T cells, making CD19 escape not easy to occur, being easier to reach the lesion site, and improving the therapeutic effects for diseases.
  • Figure 1 is a diagram showing the synthetic gene sequence map of the chimeric antigen receptor targeting CD19 and the chimeric antigen receptor targeting CD22 according to the present application;
  • Figure 2 is a graph showing the results of flow cytometry analysis of CD19 and CD22 of B cell leukemia and lymphoma cell lines;
  • Figure 3 is a graph showing the results of in vitro specific killing of B cell leukemia lymphoma cell lines with CD19-targeted and CD22-targeted chimeric antigen receptor T cells as detected by flow cytometry using Annexin V/PI;
  • Figure 4 is a graph showing the results of in vitro specific killing of B cell leukemia lymphoma cell lines with CD19-targeted and CD22-targeted chimeric antigen receptor T cells as detected by observing green fluorescent target cells under a microscope;
  • Figure 5 is a flow chart showing the clinical trial using CD19-targeted chimeric antigen receptor T cells combined with CD22-targeted chimeric antigen receptor T cells to treat B cell leukemia/lymphoma;
  • Figure 6 is a dot-plot showing the results of flow cytometric analysis of primary B-ALL cells stained with anti-CD19 and CD22 antibodies, wherein the samples were obtained from the bone marrow of three B-ALL patients;
  • Figure 7 shows the statistical analysis of the expression level of CD22 in CD19-positive cells in bone marrow malignant cells of B cell leukemia patients as detected by flow cytometry;
  • Figure 8 shows the statistical analysis of immunohistochemical staining of tissue sections of B cell lymphoma patients, wherein Fig. 8 (a) shows the distribution of CD19 expression, and Fig. 8 (b) shows the distribution of CD22 expression;
  • Figure 9 shows examples of immunohistochemical staining of CD19 and CD22 in tissue sections of patients with B cell lymphoma
  • Figure 10 shows the remission rates of 18 patients with B cell leukemia (Fig. 10 (a) ) /lymphoma (Fig. 10 (b) ) after infusion of CD19 and CD22 CAR-T cells in clinical, wherein PD represents progressive disease, PR represents partial remission, and CR represents complete remission;
  • Figure 11 shows changes in clones of bone marrow malignant cells and CD19-positive cells in patients with refractory B cell follicular lymphoma after infusion of CD19 CAR-T cells combined with CD22 CAR-T cells in clinical trial;
  • Figure 12 shows changes in lymph node size in patients after infusion
  • Figure 13 shows changes in copy numbers of CD19 and CD22 CAR in peripheral blood of patients after infusion
  • Figure 14 shows changes in lymphoma size in patient YXX after infusion as indicated by PET-CT.
  • reagents or instruments used herein which are not indicated with manufacturers, are conventional products that are commercially available from formal sources.
  • Casp9 had the nucleotide sequence as shown in SEQ ID NO. 5, and
  • Casp9 had the nucleotide sequence as shown in SEQ ID NO. 7.
  • virus supernatant was filtered with a 0.45 ⁇ m low protein-binding filter, and the virus was divided into small portions and stored at -80 °C;
  • lentiviral vectors at a titer of 10 6 to 10 7 transducing units can be produced by transduced cells per ml media.
  • the virus supernatant was added to the Centricon filter tube or the like, then centrifuged at 2500g for 30 minutes;
  • the activated T cells were seeded into a culture dish, and concentrated lentiviruses containing target genes were added, centrifuged at a centrifugal force of 100 g for 100 minutes, then cultured at 37 °C for 24 hours, and AIM-V media containing cell culture factors were added, after 2-3 days of culture, the cells were harvested and counted to produce available CD19 CAR-T cells and CD22 CAR-T cells.
  • CD19 CAR-T cells and CD22 CAR-T cells were co-cultured with RS4; 11 (RS4; 11 wassort) target cells transduced with green fluorescence proteins with a ratio of CAR-T cells to target cells of 2:1. After one hour of culture, cells were stained with Annexin V/PI, and the percentage of viable cells and dead cells were analyzed to obtain the killing efficiency of CAR-T cells.
  • Figure 5 is a flow chart showing the clinical trial using CD19-targeted chimeric antigen receptor T cells combined with CD22-targeted chimeric antigen receptor T cells to treat B cell leukemia/lymphoma. Specific steps were as follows.
  • Figure 6 is a dot-plot showing the results of flow cytometric analysis of primary B-ALL cells stained with anti-CD19 and CD22 antibodies, wherein the samples were obtained from the bone marrow of three B-ALL patients.
  • the expression of CD19 and CD22 in the three patients was higher than 60%, and was nearly 100%in patient 3.
  • CD19 and CD22 double-positive cells also exceeded 60%of malignant cells.
  • This figure showed the prevalence of CD19 and CD22 in B-ALL patients and high proportions of the same in malignant cells, so CD22 can be a very good adjuvant target for CAR-T treatment of B-ALL.
  • Figure 7 shows the scatter diagram of CD22 expression in the CD19-positive cell population in the bone marrow of 15 B-ALL patients as detected by flow cytometry staining. The results were shown in Table 1 below:
  • Figure 8 (a) - Figure 8 (b) shows the statistical analysis on immunohistochemical staining of CD19 and CD22 in tissue sections of 28 patients with B cell lymphoma.
  • the staining intensity was well-distributed, with from 1+ to 4+ each accounting for a quarter of the total number of positive patients.
  • the number of patients with a staining intensity of 3+ were the most, which again proved that CD22 was a good auxiliary target also in the CAR-T treatment of B-cell lymphoma.
  • Figure 9 shows the results of immunohistochemical staining of three different B cell lymphoma patients. Both CD19 and CD22 were consistently highly expressed in follicular lymphoma, diffuse large B lymphoma, and primary mediastinal large B-cell lymphoma.
  • Fig. 10 (a) -Fig. 10 (b) 18 patients with B-cell leukemia/B-cell lymphoma were treated, and the remission rate results were shown in Fig. 10 (a) -Fig. 10 (b) .
  • 3 of them received complete remission and 1 received partial remission, i.e., 57%patients had response to the treatment.
  • 11 patients with B-cell lymphoma 2 of them received complete remission and 5 received partial remission, i.e., 64%patients had response to the treatment.
  • Sample a 31-year-old male patient with relapsed and refractory stage IV follicular lymphoma. No therapeutic effect was achieved and the disease was progressed after several R-CHOP chemotherapies and second-line R-ESHAP chemotherapies.
  • the patient's malignant cells expressed CD20, CD22, FMC7, CD79b and CD45, and a part thereof expressed CD19 and CD23.
  • CAR-T cells were prepared according to the above procedures, and 1 ⁇ 10 6 /kg CAR-T cells were infused. Only responses less than grade 1 CRS were observed in the patient after infusion. Changes in clones of bone marrow malignant cells and CD19-positive cells after infusion were shown in Figure 11.
  • Figure 11 shows changes in the size of swollen lymph nodes caused by malignant cell proliferation after infusion of CAR-T cells. After the first infusion, the lymph nodes were significantly and continuously reduced. After the second infusion, up to 300 days after the reinfusion, the malignant swollen lymph nodes had disappeared.
  • Figure 13 shows the respective amplification of CD19 and CD22 CAR-T cells in peripheral blood of patients. On the 14th and 21st day after the first reinfusion, significant CAR-T cell amplification was observed.
  • Figure 14 shows changes in lymphoma size as indicated by PET-CT under long-term follow-up. As observed at day 62, 141 and 285 after the reinfusion, the lymphoma was continuously reduced, and no visible lymphoma was seen after nine months, suggesting that a sustained complete remission was achieved.
  • the two chimeric antigen receptors of the present application specifically recognize tumor surface antigens CD19 and CD22.
  • using two types of CAR-T cells in combination achieves better therapeutic effects, makes CD19 escape not easy to occur, and allows the disease to be easily relieved.

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Abstract

L'invention concerne un mélange de cellules immunitaires comprenant une cellule immunitaire génétiquement modifiée avec un récepteur antigénique chimérique ciblant CD19 et une cellule immunitaire génétiquement modifiée avec un récepteur antigénique chimérique ciblant CD22. Le récepteur antigénique chimérique ciblant CD19 et le récepteur antigénique chimérique ciblant CD22 comprennent chacun un domaine de liaison à l'antigène, un domaine transmembranaire, une région de signalisation costimulatrice, un domaine de signalisation de CD3ζ, et un domaine de fusion suicide inductible en agencement en tandem. Les récepteurs antigéniques chimériques reconnaissent spécifiquement des antigènes tumoraux de surface CD19 et CD22. Par comparaison avec l'utilisation d'autres lymphocytes T à récepteur d'antigène chimèrique à cible unique, l'utilisation de cellules CAR-T ciblant deux antigènes permet d'obtenir de meilleurs effets thérapeutiques, ce qui difficulte l'échappement de CD19, et permet de soulager facilement la maladie.
PCT/CN2019/122162 2018-11-30 2019-11-29 Immunothérapie à car-t combinée basée sur cd19 et cd22 Ceased WO2020108644A1 (fr)

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WO2023090704A1 (fr) * 2021-11-17 2023-05-25 (주)이노베이션바이오 Anticorps spécifique pour cd22 humanisé et récepteur antigénique chimérique l'utilisant

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CN112390891B (zh) * 2019-08-14 2022-06-03 苏州方德门达新药开发有限公司 嵌合抗原受体及其构建方法和应用
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CN114369622A (zh) * 2021-12-31 2022-04-19 西安桑尼赛尔生物医药有限公司 同时靶向cd7和cd19的双特异通用型car-t细胞及其制备方法
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