CN113122543A - Aptamer of sialic acid binding immunoglobulin-like lectin-15 protein and application thereof - Google Patents
Aptamer of sialic acid binding immunoglobulin-like lectin-15 protein and application thereof Download PDFInfo
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- CN113122543A CN113122543A CN202110358738.5A CN202110358738A CN113122543A CN 113122543 A CN113122543 A CN 113122543A CN 202110358738 A CN202110358738 A CN 202110358738A CN 113122543 A CN113122543 A CN 113122543A
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/115—Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
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- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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- C12N2310/00—Structure or type of the nucleic acid
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Abstract
The invention discloses an aptamer of Sialic acid binding immunoglobulin-like lectin-15 (Sialic acid-binding immunoglobulin-like lectin-15, Siglec-15) protein, which comprises the following components in percentage by weight as shown in SEQ ID NO: 1 to SEQ ID NO: 7. The nucleic acid aptamer can provide rapid and accurate detection of Siglec-15 protein, and simultaneously, the aptamer can block the interaction of the aptamer and a T cell surface receptor and recover the proliferation activity of T cells to a certain extent, so that the immunity of a tumor microenvironment is normalized, and the severe autoimmune reaction cannot be caused. The Siglec-15 aptamer can be used as a medicine for cancer with high expression of Siglec-15 in a tumor microenvironment, becomes a potential nucleic acid medicine for tumor immunotherapy, and is possibly effective in resisting patients with ineffective PD-L1 treatment, so that the existing tumor diagnosis and immunotherapy system is supplemented.
Description
Technical Field
The invention relates to an aptamer of Sialic acid binding immunoglobulin-like lectin-15 (Sialic acid-binding immunoglobulin-like lectin-15, Siglec-15) protein and application thereof.
Background
Cancer is a global public health problem and a significant threat to human health. With the progress of science and the development of cancer-related disciplines, research on tumor immunity and immunotherapy have been rapidly progressing. Among them, immunosuppressants represented by PD-1/L1 are most noticeable in tumor immunotherapy and bring new hopes for a large number of tumor patients, but the immunotherapy is not effective for all tumor patients, and the total effective rate of PD-1/L1 antibody to solid tumor is still about 20% in the single use case.
Sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) can mediate interaction between cells and pathogens by recognizing Sialic acid-containing sugar chain structures, and plays an important regulation role in innate immunity and adaptive immunity. The research shows that Siglec-15 mRNA is up-regulated in a plurality of cancers, including lung cancer, kidney cancer, liver cancer, colon cancer, bladder cancer, endometrial cancer and the like, and Siglec-15 is detected in tumor cells, tumor-related interstitial cells and tumor-infiltrated macrophages/bone marrow cells, and the interaction of the Siglec-15 with a T cell surface receptor can inhibit the proliferation activity of T cells, and finally, the tumor cells are subjected to immune escape. While expression of siglec-15 was mutually exclusive to PD-L1, suggesting that these two molecules might mediate immunosuppression by completely different mechanisms. Blocking siglec-15 may normalize the immunity of the tumor microenvironment, not cause severe autoimmune responses, and may be effective in patients who are refractory to anti-PD-L1 therapy.
At present, many immune checkpoint antibodies including Siglec-15 are not yet on the market, because the production cycle of antibodies is slow, and the antibodies have the disadvantages of instability, volatility and high cost, so that the development of other more stable, more effective and lower cost immunotherapeutic drugs is urgently needed. Aptamers are oligonucleotides that can bind to target molecules with high affinity and high specificity, which are obtained by in vitro screening from an artificially synthesized random oligonucleotide library, and most aptamers are obtained by screening with the Exponential Enrichment ligand Evolution technology (SELEX). The aptamer serving as a specific recognition molecule has higher specificity and affinity to a target, is simple to synthesize, convenient to modify, small in size, low in immunogenicity and low in price compared with an antibody, attracts extensive attention of basic research and application research, and has great application potential in the aspects of biosensors, imaging probes, early disease detection, pharmaceutical preparations and the like. Therefore, the development of the Siglec-15 aptamer for tumor immunotherapy is of great significance.
Disclosure of Invention
The main object of the present invention is to provide an aptamer of Siglec-15 protein, which comprises the sequence as shown in SEQ ID NO: 1 to SEQ ID NO: 7 or a nucleotide sequence shown in any one of the above.
Preferably, the aptamer is SEQ ID NO: 3.
the invention also aims to provide the aptamer of the Siglec-15 protein, and the application of the aptamer of the Siglec-15 protein in identification of the Siglec-15 protein.
The invention also aims to provide the application of the aptamer of the Siglec-15 protein in the detection of tumor cells expressing the Siglec-15 protein, tumor-associated mesenchymal cells and tumor-infiltrated macrophages/bone marrow cells.
The invention also aims to provide the application of the aptamer of the Siglec-15 protein in imaging of tumor cells expressing the Siglec-15 protein, tumor-associated mesenchymal cells and tumor-infiltrated macrophages/bone marrow cells.
The invention also aims to provide the application of the aptamer of the Siglec-15 protein in the preparation of related immunotherapy medicaments.
The invention provides a new method for Siglec-15 high-expression tumor detection and Siglec-15 mediated tumor immunotherapy by providing the nucleotide sequence as an aptamer, and supplements the existing tumor diagnosis and treatment system.
The invention is SEQ ID NO: 1 to SEQ ID NO: 7, which has a strong binding ability to Siglec-15. In particular, SEQ ID NO: 3, has high affinity to Siglec-15 protein, wherein the dissociation constant of the agarose microspheres for the Siglec-15 protein is Kd＝3.2±0.4nM。
SEQ ID NO: 3, can also maintain good binding capacity and affinity to a human brain glioma cell line (U87) with high expression of Siglec-15, and has a dissociation constant of Kd34.1 +/-4.3 nM and the selectivity is optimal.
SEQ ID NO: 3, and can identify Siglec-15 in a complex environment.
Drawings
The invention is further illustrated by the following figures and examples.
FIG. 1 shows His-tag Siglec-15 modified Ni Sepharose beads to monitor the enrichment process. The fluorescence intensity of library binding to Siglec-15-Ni-beads increased significantly with increasing number of screening rounds (FIG. 1A), however, the fluorescence intensity of Ni-beads did not increase (FIG. 1B).
FIG. 2 shows the random DNA sequence, the fluorescence intensity of the binding of the enrichment library and the 7 selected aptamers to Siglec-15-Ni agarose microspheres. It was shown that different aptamers at the same concentration all bound to Siglec-15, although their binding ability to Siglec-15 protein was different (fig. 2A); meanwhile, the obtained aptamer can keep good binding capacity to a human brain glioma cell line (U87) with high expression of Siglec-15 (FIG. 2B), wherein the sequence WXY3 has good binding capacity with U87 cells and the selectivity is optimal.
Fig. 3 shows the binding capacity of WXY3 to U87 cells in a complex system. The amount of aptamer bound to U87 cells was not significantly reduced under DMEM complete medium conditions compared to buffer (fig. 3A); furthermore, approximately 75% of the bound aptamers remained unchanged compared to the buffer under 100% human serum culture conditions (fig. 3B).
FIG. 4 shows the binding affinity of WXY3 to Siglec-15-Ni-beads, U87 cells. The binding dissociation constant of WXY3 to Siglec-15 protein was 3.2nM (fig. 4A) and 34.1nM for U87 cells (fig. 4B).
Figure 5 shows the use of WXY3 in immunotherapy. Siglec-15 inhibits about 50% CD8+T cell proliferation, CD8 in the presence of WXY3+T cell proliferative capacity returned to 93% of normal levels (fig. 5A); WXY3 enhanced CD8 to some extent+The ability of T cells to kill tumor cells (U87), U87 cell activity was approximately 55% of that of the blank (fig. 5B); WXY3 was itself less cytotoxic and U87 cell activity was 90% of blank control (fig. 5C).
Detailed Description
Example 1 screening of Siglec-15 aptamers
Chemically synthesizing an 85-base DNA initial library, wherein the two ends of the DNA initial library are fixed sequences, the random sequence with the middle of 45 bases is 5 '-AAGGAGCAGCGTGGAGGATA-45N-TTAGGGTGTGTCGTCGTGGT-3', and the library capacity is 1015The above. 5nmol of the initial DNA library was dissolved in binding buffer (12mmol/L PBS, pH 7.4, 150mmol/L NaCl, 5mmol/L KCl, 0.55mmol/L MgCl)2) Performing denaturation treatment: at 95 deg.C for 10min, ice for 10min, and then at 25 deg.C for 10 min.
2) Recombinant Siglec-15 protein expressed by poly-histidine tag (purchased from nano Biological) was used as a screening target for aptamers. The Siglec-15 protein is modified on the Ni agarose microspheres, and the Siglec-15-Ni agarose microspheres are formed by the interaction of the epitope of His-tag and Ni.
3) Incubating the obtained initial library solution with Siglec-15-Ni agarose microspheres for 30min at 25 ℃; the recovered microspheres were washed twice with binding buffer, and the recovered Siglec-15-Ni Sepharose microspheres were added to a PCR mixture containing forward primer (5 '-fam-AAGGAGCAGCGTGGAGGATA-3'), biotinylated reverse primer (5 '-biotin-ACCACGACGACACACCCTAA-3'), dNTPs, Taq DNA polymerase and PCR buffer to amplify the target sequence (pre-denaturation at 94 ℃ for 3min, 30s at 94 ℃, 30s at 60 ℃, 30s at 72 ℃, 10 cycles of amplification, and finally extension at 72 ℃ for 5 min). To obtain a single-stranded library, the PCR product was incubated with streptavidin-coated agarose microspheres and then denatured with 0.1M NaOH for 1 min. After desalting and purifying by using a 3K ultrafiltration tube, a product, namely a secondary single-stranded DNA library can be used for the next round of screening.
4) Ni sepharose microspheres were used as targets for negative screening starting from round 3 to exclude sequences bound to Ni sepharose microspheres. The screening steps are repeated, the input amount of the library and the protein Siglec-15-Ni agarose microspheres is gradually reduced in the screening process, and the input amount of the Ni agarose microspheres and the washing times are gradually increased to enhance the screening strength.
5) In this example, 11 rounds of classical SELEX screening were performed to ensure that Siglec-15 protein binds to multiple copies of the DNA strand.
Example 2 examination of binding ability and affinity of nucleic acid aptamers to Siglec-15 by flow cytometry
1) His-tag Siglec-15 modified Ni Sepharose microspheres were used to monitor the progress of enrichment. Flow-through results showed that the pool bound to Siglec-15-Ni-beads with an increase in the number of screening rounds (FIG. 1A), while the Ni-beads did not increase in fluorescence intensity (FIG. 1B), indicating that the DNA library was successfully enriched with the recognition sequence of Siglec-15 protein after 11 rounds of screening.
2) Some sequences were obtained by enrichment of library TA clone sequencing, i.e. SEQ ID NO: 1 to SEQ ID NO: WXY1, WXY2, WXY3, WXY4, WXY5, WXY6, and WXY7 shown in FIG. 7 (Table 1). FIG. 2A shows the binding of the initial library, the enrichment library and the selected 7 aptamers to Siglec-15-Ni Sepharose beads. Although the binding ability of different aptamers to the Siglec-15 protein is different, all aptamers bind to Siglec-15 at a concentration of 200 nM. FIG. 2B shows the random DNA sequences and the binding of 7 selected aptamers to a Siglec-15 positive human glioma cell line (U87). Wherein SEQ ID NO: the 3 nucleic acid aptamer can maintain good binding capacity and optimal selectivity on a human brain glioma cell line (U87) highly expressing Siglec-15.
3) For selected aptamers SEQ ID NO: 3 the binding performance of the human brain glioma cell line (U87) highly expressing Siglec-15 in DMEM complete medium and 100% human plasma was evaluated to investigate the practical application value of the selected aptamers. The amount of aptamer bound to U87 cells did not change significantly under DMEM complete medium conditions compared to buffer (fig. 3A). Furthermore, approximately 75% of the bound aptamers remained unchanged compared to the buffer under 100% plasma culture conditions (fig. 3B). These results indicate that SEQ ID NO: 3 can be combined with U87 cells in a buffer solution with high affinity, can identify Siglec-15 in a complex environment, and has good application prospect.
4) SEQ ID NO: 3 dissociation constant (K) was determined with Siglec-15 protein Sepharose microspheres, Siglec-15 positive human brain glioma cell line (U87)d) According to the formula Y ═ a X/(K)d+ X) calculating the aptamer SEQ ID NO: 3 dissociation constant. The results are shown in FIG. 3, SEQ ID NO: the dissociation constants of 3 pairs of Siglec-15 protein agarose microspheres and U87 cells are Kd3.2 ± 0.4nM (fig. 4A), Kd34.1 ± 4.3nM (fig. 4B). The results show that SEQ ID NO: 3 has high affinity for Siglec-15 protein and can therefore be used for subsequent detection, imaging or therapy.
Example 3 aptamer formation on Siglec-15/CD8+Use in T cell immunotherapy
1) CFSE stained CD8+T detection of aptamer pair CD8+Effect of T cell proliferative capacity. Addition of activated CD8 to Siglec-15 protein+T cells and different aptamers: random sequence at final concentration of 2 μ M, SEQ ID NO: 3, adding the mixture once every 12 hours. After 72 hours incubation, flow-through results showed that compared to CD8 alone+T system, adding CD8+After T cells, the viability of T cell proliferation decreased by about 50%, aptamers SEQ ID NO: 3 restores the proliferative capacity of T cells to a large extent, as CD8 alone+T (FIG. 5A).
2) Make itDetection of aptamer pair CD8 with CCK-8+Effect of T cells on cancer cell killing ability. Addition of activated CD8 to U87 cells+T cells and different aptamers: random sequence at final concentration of 2 μ M, SEQ ID NO: 3, adding the mixture once every 12 hours. After incubation for 36 hours, the supernatant in the 96-well plate was discarded and washed 2 times with DPBS, 100. mu.L DMEM and 10. mu.L CCK-8 were added to each well, the 96-well plate was incubated in an incubator at 37 ℃ for 60min, and the absorbance of the solution at 490nm was measured using a microplate reader. Addition of CD8 compared to the U87 only system+After T cells, the viability of cancer cells decreased by about 13%, at which time T cells showed poor killing ability. SEQ ID NO: 3 enhanced the killing ability of T cells to such an extent that U87 cells were approximately 55% active (fig. 5B), while the same concentrations of SEQ ID NO: u87 cell activity was about 90% under 3 conditions (fig. 5C). Description of SEQ ID NO: 3 has blocking effect on the immune escape of cancer cells, and can help CD8+T lymphocytes restore cell activity and enhance their ability to kill cancer cells.
TABLE 1
The above description is only a preferred embodiment of the present invention, and therefore should not be taken as limiting the scope of the invention, which is defined by the appended claims and their equivalents.
Sequence listing
<110> university of mansion
Nucleic acid aptamer of <120> sialic acid binding immunoglobulin-like lectin-15 protein and application thereof
<160> 7
<170> SIPOSequenceListing 1.0
<210> 1
<211> 86
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 1
aaggagcagc gtggaggata tggtagtggg tgggtggtgg ggctggctgc gttgcgtgta 60
ggagtgttag ggtgtgtcgt cgtggt 86
<210> 2
<211> 85
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 2
aaggagcagc gtggaggata tcgttggatg ggcgggtggg tttaggttat ccgacctttg 60
ctctattagg gtgtgtcgtc gtggt 85
<210> 3
<211> 85
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 3
aaggagcagc gtggaggata agcgggttgg tgggcaagag gatgtttatt tcattggtgt 60
gctgtttagg gtgtgtcgtc gtggt 85
<210> 4
<211> 85
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 4
aaggagcagc gtggaggata tcacgccggc gacgccatag cgggttggtg ggcaagaggg 60
agtttttagg gtgtgtcgtc gtggt 85
<210> 5
<211> 85
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 5
aaggagcagc gtggaggata tctcactcac tgcggtctgc gggttggtgg gcaagaggga 60
gtttattagg gtgtgtcgtc gtggt 85
<210> 6
<211> 85
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 6
aaggagcagc gtggaggata agaagagggt tggtgggcga tagggagtac taaactttaa 60
ggacattagg gtgtgtcgtc gtggt 85
<210> 7
<211> 85
<212> DNA
<213> Artificial Sequence (Artificial Sequence)
<400> 7
aaggagcagc gtggaggata ttgcgggttg gtgggcaaga gggagttatt agcacggtta 60
gtaccttagg gtgtgtcgtc gtggt 85
Claims (6)
- An aptamer for a Siglec-15 protein, characterized in that: the aptamer comprises the nucleotide sequence shown as SEQ ID NO: 1 to SEQ ID NO: 7 or a nucleotide sequence shown in any one of the above.
- 2. The aptamer of Siglec-15 protein according to claim 1, wherein: the aptamer is shown in SEQ ID NO: 3.
- 3. use of an aptamer to a Siglec-15 protein according to any one of claims 1 to 2 for the identification of Siglec-15 proteins.
- 4. Use of an aptamer to a Siglec-15 protein according to any one of claims 1 to 2 for the detection of tumor cells, tumor-associated stromal cells, tumor-infiltrating macrophages/bone marrow cells expressing the Siglec-15 protein.
- 5. Use of an aptamer to a Siglec-15 protein according to any one of claims 1 to 2 for imaging of Siglec-15 protein expressing tumor cells, tumor associated stromal cells, tumor infiltrating macrophages/bone marrow cells.
- 6. Use of an aptamer of a Siglec-15 protein according to any one of claims 1 to 2 for the preparation of a medicament for relevant immunotherapy.
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| CN116536319A (en) * | 2023-01-10 | 2023-08-04 | 广西师范大学 | Screening and application of immune checkpoint CD47 aptamer |
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