CN116019939A - Molecular probe targeting MSLN and application thereof - Google Patents

Molecular probe targeting MSLN and application thereof Download PDF

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CN116019939A
CN116019939A CN202211485309.5A CN202211485309A CN116019939A CN 116019939 A CN116019939 A CN 116019939A CN 202211485309 A CN202211485309 A CN 202211485309A CN 116019939 A CN116019939 A CN 116019939A
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msln
molecular probe
bxpc
tumor
nota
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兰晓莉
盖永康
吕小迎
宋祥铭
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Tongji Medical College of Huazhong University of Science and Technology
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Tongji Medical College of Huazhong University of Science and Technology
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Abstract

The invention relates to the field of molecular detection, and more particularly relates to a method for detecting a moleculeIn vivo, molecular probes targeting MSLN are involved. The invention claims a molecular probe targeting MSLN, which is a compound having the following sequence, or a pharmaceutically acceptable salt or lipid thereof: (QVHLVESGGGSVQTGGSLRLSCTASGLSFSTYTVAWFRQAPGKEREGVAAI PYTSQHMVYTDSVKGRFTISRDNTKNM VYLQMNSLKPEDTAMYYCATDRRPGTSMLAINGYNRWGQGTQVTVSS) m ‑R n Wherein R is selected from the group consisting of a linking group, a chelator, a radionuclide, another targeting polypeptide or monoclonal antibody, a fragment of monoclonal antibody, and a small molecule inhibitor; wherein n represents the number of R, n=0-4; wherein m is not 0. The probe has good in vitro stability, clear development in tumor and good specificity.

Description

Molecular probe targeting MSLN and application thereof
Technical Field
The present invention relates to the field of molecular detection, and more particularly to molecular probes targeting MSLN.
Background
Mesothelin is a cell surface glycosyl phosphatidylinositol anchoring protein originally characterized by Chang et al in mesothelioma and ovarian cancer using monoclonal antibody K1, which was named "mesothelin" as it was found to be produced by mesothelial cells. Mesothelin normal expression is limited to only the pleural, pericardial, peritoneal and male epithelial cells, with minimal expression also observed in the epithelial lining of the ovaries, fallopian tubes and testes. In contrast to limited expression under normal physiological conditions, MSLN has been found to be overexpressed in a broad range of solid tumors, making it an attractive tumor target. Although the biological function of MSLN is not yet clear, more and more studies confirm its involvement in various mechanisms of cancer occurrence and progression. Abnormal MSLN expression plays a positive role in malignant transformation and invasive metastasis of tumors by promoting tumor proliferation, local invasion and metastasis, and conferring resistance to cytotoxic drug-induced apoptosis to tumors. Elevated expression of MSLN has also been found to be associated with a poor prognosis for cancer patients.
Overexpression and carcinomatous effects of MSLN in a variety of solid tumors have been demonstrated, particularly for pancreatic cancer. MSLN is expressed in most pancreatic cancers, and independent studies showed that MSLN expression in nearly 100% of pancreatic cancers is positive, whereas it is not expressed in normal pancreatic tissues. Given the very small and abnormal expression of MSLN in normal tissues in many tumors, it has become a very attractive target for the development of anti-tumor therapies with low "non-tumor targeting toxicity" and with a high number of applications. Various types of anti-cancer therapies have been developed based on MSLN, including: antibodies, antibody-drug conjugates, immunotoxins, radionuclide therapy, cancer vaccines, and chimeric antigen receptor T cell therapies, among others.
Therefore, the development of the molecular probe for noninvasively tracing the MSLN of the organism is beneficial to early and real-time dynamic discovery and detection of tissues with high MSLN expression, such as pancreatic cancer tissues and the like, and has high clinical significance in the aspects of diagnosis, staging, curative effect evaluation and the like of MSLN high-expression diseases.
Thus, there remains a need in the art for a molecular probe targeting MSLN with high specificity that has better in vivo pharmacokinetic performance. It can be used for diagnosis and treatment of diseases in which MSLN is highly expressed, in particular, MSLN is highly expressed solid tumors and the like.
Disclosure of Invention
In a first aspect, the invention provides a MSLN-targeted molecular probe that is a compound having the following sequence, or a pharmaceutically acceptable salt or lipid thereof:
(QVHLVESGGGSVQTGGSLRLSCTASGLSFSTYTVAWFRQAPGKEREG VAAIPYTSQHMVYTDSVKGRFTISRDNTKNMVYLQMNSLKPEDTAMYYCAT DRRPGTSMLAINGYNRWGQGTQVTVSS) m -R n ，
wherein R is selected from the group consisting of a linking group, a chelator, a radionuclide, another targeting polypeptide or monoclonal antibody, monoclonal antibody fragment, and a small molecule inhibitor;
wherein n represents the number of R, n=0-4;
wherein m is not 0.
In some specific embodiments, m=1-4.
In some specific embodiments, the specific sequences of the molecular probes are:
QVHLVESGGGSVQTGGSLRLSCTASGLSFSTYTVAWFRQAPGKEREGVA AIPYTSQHMVYTDSVKGRFTISRDNTKNMVYLQMNSLKPEDTAMYYCATD RRPGTSMLAINGYNRWGQGTQVTVSS。
in some embodiments, the specific sequence of the molecular probe is a dimer or multimer of antibodies to the sequences described above.
In some embodiments, the linking group may modify the pharmacokinetic properties of the molecular probe in vivo, improving its distribution and metabolic levels in vivo, and may be PEGn or Glyn, where n represents a number, i.e., a degree of polymerization, and n may be from 0 to 10. The linking group may also be the remaining amino acid or polypeptide.
In some specific embodiments, the chelator may be coordinated to the functional metal, the chelator may be DOTA, NOTA, NETA, AATZA, or Hynic and derivatives thereof.
In some embodiments, the radionucleic acid may be a positive electron core for PET imaging, e.g 68 Ga、 18 F-Al( 18 Aluminum fluoride), 64 Cu、 89 Zr; single photon nuclides for SPECT imaging, e.g 99m Tc、 111 In; paramagnetic metals may also be used for MRI imaging, such as Gd, mn, etc., and beta or alpha nuclides for nuclide targeted therapy, such as 188 Re、 186 Re、 177 Lu、 90 Y、 223 Ra, etc.
In some specific embodiments, the small molecule inhibitor may be a small molecule drug.
In some specific embodiments, the small molecule inhibitor may be a drug for treating cancer.
In some specific embodiments, the small molecule inhibitor may be doxorubicin, cisplatin, vinblastine, camptothecin, paclitaxel, and the like.
In some specific embodiments, the small molecule inhibitor may be MK-0429, sorafenib, imatinib, gefitinib, and the like.
The MSLN-targeted molecular probe has good in-vitro stability, clear development in tumor and good specificity.
In a second aspect, the present invention provides the use of a molecular probe as described above in the preparation of a kit for molecular imaging.
The invention provides application of the molecular probe in preparing a kit for diagnosing cancer.
The invention provides the use of the molecular probe in the preparation of a reagent for treating cancer.
Further, the cancer is a cancer with high MSLN expression.
In some specific embodiments, the cancer is mesothelioma, pancreatic cancer, ovarian cancer, lung cancer, cholangiocarcinoma, gastric cancer, colon cancer, thymus cancer, esophageal cancer, breast cancer, endometrial cancer, and the like.
In a specific embodiment, the cancer is pancreatic cancer.
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FIG. 1 is a radio-HPLC chart of (A) 68Ga-NOTA-MS 3; (B) 1h in vitro PBS stability; (C) 2h in vitro PBS stability; (D) 1h in vitro FBS stability; (E) 2h in vitro FBS stability;
FIG. 2 shows the expression of MSLN in BxPC-3, huH-7 and BxPC-3ko cells (beta-actin as an internal control) by Western blot analysis. (B) At time points 0.5,1 and 2h, bxPC-3, huH-7 and BxPC-3ko cell pairs 68 Uptake of Ga-NOTA-MS 3. (data are expressed as mean ± standard deviation, ×p<0.05，**p<0.01，***p<0.001)；
FIG. 3 shows (A) tail vein injection 68 Ga-NOTA-MS3 30min,1h and 2h time points BxPC-3 PET/CT images (coronal position) of tumor-bearing mice. (B) Tail vein injection 68 Ga-NOTA-MS3 30min,1h and 2h time points HuH-7 PET/CT images (coronal position) of tumor-bearing mice. (C) BxPC-3 and HuH-7 tumor pairs 68 Quantitative analysis of ROI uptake by Ga-NOTA-MS3 (n=4). (D, E) BxPC-3 and HuH-7 tumor model 68 Quantitative analysis of T/M and T/B of Ga-NOTA-MS3 (n=4). (data are expressed as mean ± standard deviation, ×p<0.05，**p<0.01，***p<0.001)；
FIG. 4 shows (A) tail vein injection 68 PET/CT images of Ga-NOTA-MS3 30min,1h,2h,3h and 4h time points BxPC-3 and BxPC-3ko bilateral tumor models. (B) BxPC-3 and BxPC-3ko tumor pairs 68 Semi-quantitative analysis of Ga-NOTA-MS3 uptake (n=4).(data are expressed as% ID/g mean.+ -. Standard deviation,.+ -. P)<0.05，**p<0.01，***p<0.001)；
FIG. 5 is (A) 68 Biodistribution study of BxPC-3 and HuH-7 tumor bearing mice after 4h of Ga-NOTA-MS3 injection. (B) BxPC-3 and HuH-7 tumors 68 Ga-NOTA-MS3 uptake, T/M and T/B. (C) 68 Biodistribution study of BxPC-3 and BxPC-3ko bilateral tumor models after 4h of Ga-NOTA-MS3 injection. (data are expressed as mean ± standard deviation, ×p<0.05，**p<0.01，***p<0.001)。
Detailed Description
The advantages and various effects of the present invention will be more clearly apparent from the following detailed description and examples. It will be understood by those skilled in the art that these specific embodiments and examples are intended to illustrate the invention, not to limit the invention.
Example 1 preparation of molecular probes
1.1 coupling of NOTA-MS3
Recombinant protein MS3 is a single domain antibody (sdAb) developed to target Mesothelin (MSLN), with a molecular weight of about 15 kDa. MS3 was conjugated with the chelator p-SCN-Bn-NOTA as follows. Briefly, nanobody was purified by PD-10desalting column (PD-10 Desalting Columns) to remove stock solution, and concentrated by ultrafiltration, followed by concentration with 0.1M Na 2 CO 3 The pH of the antibody solution was adjusted to 9-10. Chelating agent was dissolved in dimethyl sulfoxide (DMSO) and immediately followed by chelating agent and sdAb 10:1 to add the chelating agent to the antibody solution. After incubation for 2h at room temperature, the product was purified using a PD-10desalting column and concentrated by ultrafiltration. The concentrated antibody solution was stable for at least 3 months at 4 ℃.
1.2、 68 Radiolabelling and identification of Ga-NOTA-MS3
Will 1mL 68 Ga leacheate (0.05M HCI,370-555 MBq) was mixed with 300. Mu.L sodium acetate buffer (0.25M, pH 6.8) and 100-200. Mu.g of NOTA-sdAb was added to the radiometal solution. The mixture was reacted at 37℃with constant temperature shaking at 600rpm for 5-10min and the final radiopharmaceutical was purified using a PD-10desalting column. Determination of labelling Rate and radiochemistry by analytical radio-HPLCPurity of the product. Elution conditions for the Siemens Zenix-C SEC-300 size exclusion chromatography column: the temperature was 25℃and the flow rate was 1mL/min, the detection wavelength was 260nm, 280nm, and the mobile phase was 150mM PBS (Phosphate Buffered Saline).
EXAMPLE 2, 68 Radiochemical characterization and in vitro stability of Ga-NOTA-MS3
Respectively taking 3.70MBq 68 Ga-NOTA-MS3 was added to 100. Mu.L PBS and 100. Mu.L fetal bovine serum (Fetal Bovine Serum, FBS), and incubated for 1h and 2h at room temperature. Samples of PBS and FBS were taken directly for radio-HPLC identification and elution conditions were the same as in example 1.
Prepared by 68 Ga-NOTA-MS3 was identified and characterized by analytical radio-HPLC. 68 The non-decay corrected labelling rate for Ga-NOTA-MS3 was 0.47±0.02 (n=4), with a radiochemical purity greater than 98% (fig. 1A). 68 Ga-NOTA-MS3 was identified by radio-HPLC after incubation with PBS and FBS for 1h and 2h, respectively, as shown in FIGS. 1B-E, the radiochemical purity of the probe was still greater than 95%, demonstrating that 68 Ga-NOTA-MS3 is very stable in vitro.
Example 3 in vitro cellular uptake of molecular probes
The human pancreatic cancer cell line BxPC-3 and the corresponding MSLN gene knockout cell line BxPC-3ko are given away by the basic medical college of China university of science and technology, and the human liver cancer cell line HuH-7 is purchased from the cell bank of the typical culture preservation committee of China academy of sciences. BxPC-3, bxPC-3ko and HuH-7 cells were cultured in a normal high-sugar DMEM medium containing 10% fetal bovine serum and a mixture of 1% penicillin (100U/mL) and streptomycin (0.1 mg/mL) at 37℃with 5% CO 2 Culturing under the condition. BxPC-3, bxPC-3ko and HuH-7 cells are cultured in a cell culture dish, and when the cells are in logarithmic growth phase and grow to 75% -85%, total proteins are extracted. Protein concentration was determined using BCA kit and SDS-PAGE concentrate and separator gels were prepared in conventional proportions. And adding the prepared protein sample to be detected and a Marker into a sample loading hole, wherein the total protein loading amount of each sample is 40 mug, and performing SDS-PAGE electrophoresis. After the electrophoresis, the membrane was transferred and the PVDF membrane was closed. The primary anti-rabbit anti-Mesothelin antibody monoclonal antibody was diluted 1:1000 and then incubated with PVDF membrane overnight at 4 ℃. And then incubating with a secondary antibody normal temperature shaking table for 1h, and developing. By usingImage J software determines the grey value of the band.
Logarithmic growth phases of BxPC-3, bxPC-3ko and HuH-7 cells were counted and then at 2X 10 per well 5 Individual cells were seeded in 24-well plates and cultured overnight. The culture broth was discarded, and 800. Mu.L of DMEM medium free of serum and diabodies was added to each well for further culture for 1 hour. Then 50. Mu.L of 74KBq of each well was added 68 Ga-NOTA-MS3 were incubated in an incubator at 37℃for 1h and 2h (4 duplicate wells were set per time point). At the end of incubation, the supernatant was collected in tubes, and each well was washed once with pre-chilled PBS and collected in the same tube. Subsequently, cells were lysed by adding 800. Mu.L NaOH solution (1M) to each well for 5min, and the cell lysates were collected in another tube, washed once with PBS, and collected in the same tube. The radioactivity count of each tube was measured with a fully automatic gamma counter. Cell mass fraction was expressed as: cell radioactivity count/(supernatant radioactivity count + cell radioactivity count) ×100%.
Cell target protein expression was assessed by Western blot, as shown in FIG. 2A, bxPC-3 cells expressed MSLN relatively high, and HuH-7 and BxPC-3ko cells expressed MSLN relatively low.
By comparing BxPC-3, huH-7 and BxPC-3ko cell pairs 68 Uptake of Ga-NOTA-MS3 assessed its targeting efficiency at the cellular level. As shown in FIG. 2B, bxPC-3 pair at 1h and 2h 68 Ga-NOTA-MS3 uptake was 0.69+ -0.15% and 0.71+ -0.13%, respectively, significantly higher than HuH-7 uptake by 0.34+ -0.04% (p)<0.05)，0.43±0.01％(p<0.05 0.46.+ -. 0.03% of BxPC-3ko (1 h, p)<0.05)。
Example 4 PET/CT imaging of molecular probes
All animal studies were conducted following guidelines of the institutional animal care and use committee of the university of science and technology, w.c. Female Balb/c nude mice (4-5 weeks old) were purchased from Beijing Fukang Biotechnology Co., ltd and kept in the national university of science and technology Shake medical laboratory animal center SPF-grade environment.
The cells BxPC-3, bxPC-3ko and HuH-7, growing in log phase, were collected, digested with conventional pancreatin, and cell pellet was collected and counted. Subsequently, the mixture was washed twice with pre-chilled PBS and collected by centrifugationCell precipitation. Cells were resuspended in PBS at an inoculation volume of 100. Mu.L/mouse, cells were thoroughly blown, and then inoculated subcutaneously in the armpit of the right or left upper limb of mice, each mouse being inoculated 1X 10 7 Individual cells. When the tumor diameter is 8mm-10mm, the tumor is used as a subsequent experiment.
Selecting BxPC-3 cells with high MSLN expression and HuH-7 cells with low MSLN expression, constructing BxPC-3ko cells to prepare tumor model for evaluating probe 68 In vivo targeting specificity of Ga-NOTA-MS 3. Mice of each group (n=4) were injected via tail vein 68 Ga-NOTA-MS3 (-5.55 MBq, 150. Mu.L), PET/CT scan (10 min PET scan+2 min CT scan) was performed after 30min,1h and 2h. After the scanning is finished, the PET image and the CT image are reconstructed through attenuation correction, the region of interest (Region of interest, ROI) is delineated, and corresponding uptake values (percentages of the injected dose per gram of tissue,% ID/g) are calculated.
To evaluate 68 Ga-NOTA-MS3 in vivo targeting specificity, PET/CT static imaging is performed by using BxPC-3, huH-7 tumor-bearing mice and double-sided tumor models of BxPC-3 and BxPC-3 ko. Intravenous injection via tail 68 Ga-NOTA-MS is respectively subjected to PET/CT static scanning after 30min,1h and 2h. As shown in FIG. 3A, injection 68 After only 30min, the BxPC-3 tumor was clearly developed; background tissue uptake was significantly reduced at 1h and 2h, tumor uptake was also reduced, but tumor To Background Ratio (TBR) was gradually increased and tumor contours were clearer. HuH-7 tumor in injection 68 Ga-NOTA-MS shows lower uptake after 3 min; over time, both the tumor and the imaging agent in the background tissue cleared rapidly, with tumor uptake approaching background uptake (fig. 3B). Injection of 68 After Ga-NOTA-MS3 radioactivity accumulates predominantly in the kidneys and bladder, indicating that the probe is metabolized predominantly by the kidneys (FIGS. 3A and B). And (3) performing ROI delineation and quantitative analysis on the tumor tissue region through the tomographic image. As shown in FIGS. 3C-E, bxPC-3 pair 68 Tumor uptake (tumor uptake) and tumor to background ratios of Ga-NOTA-MS3, including tumor to muscle (T/M) and tumor to blood (T/B) were significantly higher than HuH-7 tumors (Table 1).
TABLE 1, 68 Ga-NOTA-Semi-quantitative analysis of PET/CT images of MS3 injected for 30min,1h and 2h time points BxPC-3 and HuH-7 tumor-bearing mice.
Figure BDA0003961963710000081
Data are expressed as mean ± standard deviation (n=4).
To further confirm 68 Ga-NOTA-MS3 in vivo specificity targeting ability, bxPC-3 and corresponding MSLN gene knockout cells BxPC-3ko are utilized to construct a bilateral tumor model for PET/CT imaging. As shown in FIG. 4A, injection 68 After Ga-NOTA-MS for 30min, bxPC-3 and BxPC-3ko tumors are developed, and the outline is clear. With metabolism of the probe, bxPC-3 tumor profile was still quite clear by 1,2 hours, bxPC-3ko tumor uptake was reduced and the development was unclear. After 3,4h of probe injection, bxPC-3 tumor uptake was reduced but the contour was still visible, whereas BxPC-3ko tumor uptake was close to the global background. ROI delineation and semi-quantitative analysis of tumor region by tomographic image, as shown in FIG. 4B, bxPC-3 tumor pair 68 Ga-NOTA-MS3 uptake at 30min,1h,2h,3h and 4h was 1.10+ -0.21%ID/g, 1.09+ -0.13%ID/g, 0.93+ -0.14%ID/g, 0.88+ -0.17%ID/g and 0.86+ -0.18%ID/g, respectively, all significantly higher than BxPC-3ko tumor (0.65+ -0.13%ID/g p)<0.05、0.54±0.08％ID/g p<0.001、0.43±0.05％ID/g p<0.001、0.37±0.15％ID/g p<0.01 and 0.35.+ -. 0.15% ID/gp<0.01 (n=4 per group).
Example 5 biological distribution of molecular probes
The biodistribution study group was consistent with the PET/CT imaging group. Each group of model mice (n=4) was injected with either probe or probe plus blocker alone via the tail vein at a probe dose of 5.55-7.4MBq (150 μl), and after 90min, mice were sacrificed at cervical dislocation and tissues or organs of interest were collected: blood, brain tissue, heart, lung, liver, spleen, kidney, stomach, small intestine, large intestine, muscle, bone, whole tail, tumor tissue, and pancreas. The tissues or organs were washed, weighed, and their radioactivity counts (counts per minute, CPM) were measured with a fully automated gamma counter. After performing attenuation correction, the uptake value of each tissue or organ is expressed as: percentage of injected dose per gram of tissue (% ID/g) =
Figure BDA0003961963710000091
The biodistribution study group was consistent with PET/CT imaging. Was performed using BxPC-3, huH-7 tumor-bearing murine models and a bilateral tumor model constructed using BxPC-3ko 68 Biodistribution of Ga-NOTA-MS3 probes was studied and compared. Each tumor-bearing mouse is injected by tail vein 68 Mice were sacrificed 4h after Ga-NOTA-MS3 (-5.55 MBq) for biodistribution studies (n=3 per group). As shown in FIGS. 5A and B, bxPC-3 tumor pairs 68 Uptake of Ga-NOTA-MS3 (0.68+ -0.16% ID/g vs 0.24+ -0.01% ID/g, p)<0.05 T/M (9.13+ -1.04 vs 6.44+ -1.20, p)<0.05 T/B (3.48.+ -. 0.45vs 1.12.+ -. 0.12, p)<0.001 Is significantly higher than HuH-7 tumors. In the biodistribution study of the bilateral tumor model, bxPC-3 tumor pairs 68 Ga-NOTA-MS3 uptake was also higher than BxPC-3ko tumor (0.67.+ -. 0.19% ID/g vs 0.41.+ -. 0.11% ID/g). 68 Ga-NOTA-MS3 uptake in the kidney was highest, consistent with imaging results, further illustrating 68 Ga-NOTA-MS3 is metabolized primarily by the kidney (FIGS. 5A and C).

Claims (10)

1. A molecular probe targeting MSLN, the molecular probe being a compound having the sequence:
(QVHLVESGGGSVQTGGSLRLSCTASGLSFSTYTVAWFRQAPGKEREG VAAIPYTSQHMVYTDSVKGRFTISRDNTKNMVYLQMNSLKPEDTAMYYCAT DRRPGTSMLAINGYNRWGQGTQVTVSS) m -R n ，
wherein R is selected from the group consisting of a linking group, a chelator, a radionuclide, another targeting polypeptide or monoclonal antibody, monoclonal antibody fragment, and a small molecule inhibitor;
wherein n represents the number of R, n=0-4;
wherein m is not 0.
2. The MSLN-targeting molecular probe of claim 1 wherein the specific sequence of the molecular probe is:
QVHLVESGGGSVQTGGSLRLSCTASGLSFSTYTVAWFRQAPGKEREGVA AIPYTSQHMVYTDSVKGRFTISRDNTKNMVYLQMNSLKPEDTAMYYCATD RRPGTSMLAINGYNRWGQGTQVTVSS。
3. the MSLN-targeting molecular probe of claim 1 wherein the linking group is PEGn, glyn, or the remaining amino acids or polypeptides, wherein n is 0-10.
4. The MSLN-targeted molecular probe of claim 1 wherein the chelator is DOTA, NOTA, NETA, AATZA, or Hynic.
5. The MSLN-targeted molecular probe of claim 1 wherein the radionuclide is a positron nuclide, a single photon nuclide, or a paramagnetic metal.
6. The MSLN-targeted molecular probe of claim 1 wherein the radionuclide is a beta or alpha particle releasing nuclide.
7. The MSLN-targeted molecular probe of claim 1 wherein the radionuclide is 68 Ga、 18 F-Al、 64 Cu、 89 Zr； 99m Tc、 111 In；Gd、Mn； 188 Re、 186 Re、 177 Lu、 90 Y、 223 Ra。
8. Use of a MSLN-targeted molecular probe of any one of claims 1-7 in the preparation of a kit for molecular imaging.
9. Use of a MSLN-targeted molecular probe of any one of claims 1-7 in the preparation of a kit for the diagnosis of cancer.
10. Use of a MSLN-targeted molecular probe of any one of claims 1-7 in the preparation of a reagent for the treatment of cancer.
CN202211485309.5A 2022-11-24 2022-11-24 Molecular probe targeting MSLN and application thereof Pending CN116019939A (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
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CN109678960A (en) * 2019-01-15 2019-04-26 天津医科大学 A kind of MSLN specificity fluorescent probe and its application
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US20110027268A1 (en) * 2007-11-26 2011-02-03 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin antibodies and uses thereof
CN103819559A (en) * 2013-12-10 2014-05-28 中国科学院武汉病毒研究所 Anti-mesothelin nanometer antibody as well as coding gene and application thereof
CN112639102A (en) * 2018-08-29 2021-04-09 南京传奇生物科技有限公司 Anti-mesothelin Chimeric Antigen Receptor (CAR) constructs and uses thereof
CN109678960A (en) * 2019-01-15 2019-04-26 天津医科大学 A kind of MSLN specificity fluorescent probe and its application

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