CN115721741A - PD-L1-targeted PET (polyethylene terephthalate) developer as well as preparation method and application thereof - Google Patents
PD-L1-targeted PET (polyethylene terephthalate) developer as well as preparation method and application thereof Download PDFInfo
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- CN115721741A CN115721741A CN202211410067.3A CN202211410067A CN115721741A CN 115721741 A CN115721741 A CN 115721741A CN 202211410067 A CN202211410067 A CN 202211410067A CN 115721741 A CN115721741 A CN 115721741A
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Abstract
The invention discloses a PD-L1-targeted PET imaging agent and a preparation method and application thereof. The PET imaging agent of the invention is Durva-F (ab') 2 The antibody fragment is modified by acylating agent 3- (4-hydroxyphenyl) propionic acid-N-succinamide ester and then is subjected to 124 I obtained by labelling 124 I‑HPP‑Durva‑F(ab') 2 Polypeptide molecular probes. The invention relates to a modified Durva-F (ab') 2 After the antibody fragment is modified by SHPP amidation, the blood clearance speed and the labeling specific activity of the probe are improved. The molecular probe of the invention has obviously reduced molecular weight, accelerates the clearance speed of the probe in vivo and is beneficial to clinical transformation. The molecular probe is applied to liver and bone tissuesThe non-specific intake of the intermediate has obvious reduction, and has greater clinical significance for patients with metastatic or primary focus positions in the part.
Description
Technical Field
The invention relates to a PD-L1-targeted PET imaging agent, and a preparation method and application thereof, belonging to the technical field of radiopharmaceutical chemistry.
Background
The anti-PD-1/PD-L1 therapy means that the interaction of PD-1 and PD-L1 is blocked by an antibody, an inhibitor and the like, and the activation of T cells is recovered, so that the reactivation of anti-tumor immunity is mediated. It is important in the treatment of a variety of tumors, especially solid tumors. anti-PD-1/PD-L1 monoclonal antibodies, such as Pembrolizumab, nivolumab, atezolizumab and Durvalumab have shown clinical application prospects in advanced cancer patients. Before treatment, patients are often examined by Immunohistochemistry (IHC) for expression of PD-L1 in primary or metastatic foci to determine if anti-PD-1/PD-L1 treatment is appropriate. In a retrospective study, IHC results were only associated with prognosis in less than 29% of patients, for reasons that may include the following: spatiotemporal heterogeneity of pd-L1 expression; 2. limitations of specimen collection; 3. the ability of different tumors to drive immunogenicity may vary. Therefore, a method combining high sensitivity and high specificity is urgently needed for detecting the expression of PD-L1.
To address this problem, physicians have conducted many meaningful studies, such as optical imaging, photoacoustic imaging, magnetic resonance imaging, and nuclear medicine imaging. Among them, nuclear medicine imaging seems to be the most feasible solution. immune-Positron Emission Tomography (immunoPET) refers to the non-invasive evaluation of the expression of a target in a lesion by acquiring the distribution of a radionuclide labeled tracer through PET imaging, and combines the extraordinary targeting specificity and affinity of a precursor and the excellent imaging sensitivity and resolution of PET. With the clinical application of long-half-life nuclides and the increasing popularity of antibody development, immuno-PET imaging has undertaken increasingly important tasks in assessing biomarker expression and predicting the likely efficacy of treatment. In one treatment of 25 different types of locally advanced or metastatic cancer patients 89 The research result of Zr-DFO-Atezolizumab immune PET imaging shows that the immune PET can not only evaluate the expression of PD-L1, but also predict the clinical response of a patient to immune blocking treatment. However, due to the characteristics of the labeling method and the antibody itself, there are limitations on 89 The Zr marked Atezolizumab is applied to the focus of a patient in liver, bone and other parts, while the anti-PD-L1 immunotherapy is mainly applied to a patient in a local advanced stage or with far distance in the cancer field, and the liver and the bone are common cancer metastasis parts of the patient. 124 I and 89 zr is both a solid target positive electron nuclide with a long half-life period, and 89 the difference between Zr and Zr is that, 124 the label of I does not need a chelating agent and can directly react with tyrosine in protein molecules. Previous studies have shown that 124 The biological characteristics of the product marked by I and the marked object are closer, and the liver and spleen uptake of the product is obviously lower than that of the marked object 89 Zr is a product marked by a chelating agent, and the cell retention and bone adsorption effects of the non-metal nuclide are obviously lower than those of the metal nuclide. Durvalumab (Durva) is another anti-PD-L1 antibody, which, unlike Atezolizumab, has relatively low hepatic uptake.
F(ab') 2 Fragments can be produced by enzymatic digestion of intact antibodies, reducing the molecular weight from around 150kDa to around 100 kDa. Comparison with intact antibody, F (ab') 2 The fragments exhibit a faster blood clearance rate while retaining high binding affinity and specificity.
In previous studies, we successfully synthesized a PET imaging agent targeting PD-L1 124 I-Durva-F(ab') 2 ( 124 I-Labeled Monoclonal Antibody and Fragment for the Noninivative Evaluation of Tumor PD-L1 Expression In Vivo), however, its future application is limited due to its relatively low specific activity and high blood accumulation.
Disclosure of Invention
The purpose of the invention is: aiming at the problems and defects of the prior PET imaging agent targeting PD-L1, the method provides and synthesizes the PET imaging agent 124 I-labeled PD-L1-targeting molecular probe 124 I-HPP-Durva-F(ab') 2 The molecular probe is used for noninvasive evaluation of focus PD-L1 expression condition and guidance of clinical medication 124 I-HPP-Durva-F(ab') 2 The targeting of PD-L1 has been verified through in vivo and in vitro experiments. The biodistribution and PET/CT imaging results show that the probe can be highly specificThe expression condition of PD-L1 is evaluated in different places, compared with the prior positron medicine, the molecular probe has obviously reduced uptake in liver and bone, and the specific activity and the blood activity are compared with those of the prior positron medicine 124 I-Durva-F(ab') 2 The improvement is also obvious.
In order to achieve the above objects, the present invention provides a labeled precursor of a PET imaging agent targeting PD-L1, which is Durva-F (ab') 2 The antibody fragment is obtained by modifying an acylating agent 3- (4-hydroxyphenyl) propionic acid-N-succinamide ester, and the structural formula is shown as a formula I, wherein Durva-F (ab') 2 The light chain amino acid sequence of the antibody fragment is shown as SEQ ID NO:1, and the heavy chain amino acid sequence is shown as SEQ ID NO:2, the acylation group SHPP is modified in Durva-F (ab') 2 Free amino groups at one or more lysine sites of the light chain and/or heavy chain of the antibody fragment,
Durva-F(ab') 2 light chain amino acid sequence of antibody fragment (SEQ ID NO: 1): EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFELTISALEPEDFAVYYCQQYGSLPWTFGQGTKVEIKRTVPAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC;
Durva-F(ab') 2 heavy chain amino acid sequence of antibody fragment (SEQ ID NO: 2): EVQLVESGGGLVQPGGSLRLSCANSGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT.
The invention also provides a PET imaging agent targeting PD-L1, which is prepared by passing the labeled precursor 124 I is obtained after radiochemical labelling, wherein 124 I is marked on the acylation group and/or the ortho-position of the benzene ring hydroxyl group on the tyrosine, wherein, one ortho-position of the benzene ring hydroxyl group is marked with 124 I or both ortho-positions are simultaneously marked with 124 I。
The invention also provides application of the labeled precursor of the PET imaging agent targeting PD-L1 in preparation of a diagnostic reagent/medicament for labeling a diagnostic nuclide and/or a therapeutic medicament.
The invention also provides a preparation method of the PD-L1 targeted PET imaging agent, which comprises the following steps:
step 1: the Dewaruzumab Durvalumab is subjected to enzyme digestion to remove Fc fragment, and the antibody fragment Durva-F (ab') with the target function is obtained after purification 2 ；
Step 2: carrying out amidation reaction on the obtained antibody fragment and acylating agent 3- (4-hydroxyphenyl) propionic acid-N succinamide ester, and purifying to obtain a modified product HPP-Durva-F (ab') 2 ；
And 3, step 3: subjecting the modified product obtained above to 124 I radiolabeling, purifying to obtain 124 I-HPP-Durva-F(ab') 2 Polypeptide molecular probes.
The invention also provides application of the PD-L1 targeted PET imaging agent in preparation of diagnostic reagents/medicaments and/or therapeutic medicaments for PD-L1 high-expression tumors, wherein the tumors comprise primary tumors or metastatic tumors.
Preferably, the primary tumor comprises a primary tumor with a focal location in the liver or bone.
The invention also provides application of the PD-L1 targeted PET imaging agent in preparation of a diagnosis and treatment kit for PD-L1 high-expression tumors.
Compared with the prior art, the invention has the beneficial effects that:
(1) In view of the fact that the targeted PD-L1 imaging agent reported in the existing literature has high uptake in the liver and bones, the evaluation of the part of patients with metastasis or primary focus position in the liver and bones is not facilitated; the invention utilizes the characteristic that the durvalumab is combined with PD-L1 with high affinity and specificity to reform the structure of the durvalumab. Retention of active region F (ab') 2 Removing the heavy chain fixed region Fc, reducing the molecular weight of the probe while keeping the specificity of the molecule, and modifying the obtained Durva-F (ab') 2 After the antibody fragment is subjected to amidation modification by SHPP, the blood clearance speed and the labeling specific activity of the probe are improved, and the defects that the application of the conventional PET probe prepared by a direct labeling method is limited by relatively low specific activity and high blood accumulation are overcome;
(2) The PD-L1 targeted PET imaging agent reserves the functional region F (ab') of the monoclonal antibody Durvallumab 2 The molecular weight is obviously reduced from the molecular weight of about 146.3kDa of the complete antibody to about 100kDa, the clearance speed of the probe in vivo is accelerated, the clinical transformation is facilitated, an image for diagnosis can be obtained within 4 hours, the 24-hour imaging effect is the best, the complete antibody can provide an image for diagnosis within 24 hours, and the best imaging time is about 96 hours;
(3) The non-specific uptake of the PET molecular probe in liver and bone tissues is obviously reduced, and the two parts are parts which are easy to generate primary or metastatic cancer foci, so that the characteristics of the imaging agent have greater clinical significance for patients who have the requirement that the position of the metastatic or primary cancer foci is positioned in the parts; compared with the probe prepared by direct labeling, the PET molecular probe of the invention has higher tumor contrast and labeling specific activity.
Drawings
FIG. 1 shows a molecular probe of the present invention 124 I-HPP-Durva-F(ab') 2 Synthetic roadmaps of (a);
FIG. 2 shows Durva-F (ab') 2 SDS-PAGE analysis of the solutions: lane M: a labeled protein of kilodalton; lane 1: non-reducing Durva-F (ab') 2 (ii) a Lane 2: reduced Durva-F (ab') 2 ；
FIG. 3 shows Durva-F (ab') 2 The mass spectrometry result of (2);
FIG. 4 is a graph of Durva-F (ab') 2 Performing HPLC analysis on the result;
FIG. 5 shows mass spectrometry of HPP-Durva-F (ab') 2 Results of the number of SHPPs connected;
FIG. 6 is a drawing showing 124 I-HPP-Durva-F(ab') 2 The radiochemical purity analysis result (A), the stability analysis (B to E) and the specific activity comparison (F) of (A); it is provided withIn (1), 124 I-HPP-Durva-F(ab') 2 the stability assays of (a) are assay result (B) incubated in PBS for 24 hours, assay result (D) incubated in PBS for 72 hours, assay result (C) incubated in FBS for 24 hours, and assay result (E) incubated in FBS for 72 hours, respectively;
FIG. 7 is a drawing showing 124 I-HPP-Durva-F(ab') 2 Biodistribution map of (a);
FIG. 8 shows tumor-bearing mice injection 124 I-HPP-Durva-F(ab') 2 MIP (left) and PET/CT (right) images after 48 h.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below with reference to the accompanying drawings.
Example 1
124 I-HPP-Durva-F(ab') 2 The preparation of (1):
mu.g intact Durva were incubated with 200U of IdeS protease in digestion buffer (20 mM sodium phosphate, 10mM sodium chloride, pH = 6.5) at 37 ℃ for 120 min. The digestion product was incubated with protein A magnetic beads for 2 hours at room temperature, and then placed in a magnetic rack for 1 minute to separate the Fc fragment-attached beads from those containing F (ab') 2 Supernatant of the fragment to obtain purified F (ab') 2 And (3) fragment. The purified F (ab') 2 Mixing the fragment with SHPP reagent, and incubating at 35-40 deg.C for 80-160min to obtain reaction product; separating and purifying the reaction product by a 7k centrifugal column to obtain HPP-Durva-F (ab') 2 。 124 I is the passage in a Sumitomo HM-20 cyclotron 124 Te(p,n) 124 I is produced by reaction. The product was heated and collected in a preconfigured NaOH solution (10 mm, ph = 12). Prior to labeling, HCl (0.1m, ph = 1) was added to the radioiodinated solution to neutralize NaOH. Subsequently, 10 XPBS (0.1M, pH = 7.4), durva-F (ab') 2 Fragment solution (. About.2 mg/mL) and 124 solution I (111 MBq/mL, pH 7.0-7.2) was added to an iodinated tube precoated with 100. Mu.g Iodogen. Incubate at room temperature for 15 minutes, gently shake every 5 minutes. 124 I-HPP-Durva-F(ab') 2 Purified by pre-equilibrated PD-10 desalting column and eluted to the column with PBSIn the heart tube, 0.5mL of the eluate was collected in each centrifuge tube in turn, and the radioactivity of each tube was measured by a gamma counter, thereby determining the location of the product (typically, tubes 4 to 6).
Example 2
124 I-HPP-Durva-F(ab') 2 Quality control and stability test:
SDS-PAGE was performed using 12% non-reducing gel at 120V for 1 hour, and the loading order of the lanes was as shown in FIG. 2, followed by staining with Coomassie Brilliant blue at Room Temperature (RT). HPLC chromatography column model on Agilent 1260Infinity II system: tosoh Bioscience TSKgel G3000SWXL (7.8mm. Times.30cm). Mass spectrometry was performed using a Waters biocord mass spectrometer.
SDS-PAGE results showed that the intact Durva antibody is located at approximately 150kDa, which is very close to the theoretical molecular weight, and after purification, durva-F (ab') 2 A single band of about 100kDa was observed in the lane of (1) (FIG. 2). Subsequently, the mass spectrometry results confirmed that Durva-F (ab') 2 Has a molecular weight of 98.544kDa (FIG. 3). SEC-HPLC analysis showed Durva-F (ab') 2 The retention time of (a) was a main peak of 8.0 to 10.0 minutes (fig. 4). HPP-Durva-F (ab') 2 The number of linked SHPPs was analyzed using mass spectrometry (fig. 5). After labeling was analyzed using iTLC 124 I-HPP-Durva-F(ab') 2 The radiochemical purity (FIG. 6A), the label stability (FIGS. 6B to 6E) and the specific activity (FIG. 6F). The labeled product has high radiochemical purity (more than 98 percent) and specific activity of about 3.0 GBq/. Mu.mol. To prove that 124 I-HPP-Durva-F(ab') 2 The probe is incubated in PBS or FBS at 37 ℃ for 24 hours or 72 hours. The results of iTLC showed that, even after 72h incubation, 124 I-HPP-Durva-F(ab') 2 is still of radiochemical purity>93 percent. Generated by direct labelling 124 I-Durva-F(ab') 2 In contrast, the labeling is carried out after modification by SHPP 124 I-HPP-Durva-F(ab') 2 The specific activity of the compound is obviously improved.
Example 3
124 I-HPP-Durva-F(ab') 2 Biodistribution experiment of (1):
in the process of injection 124 I-labelled HPP-Durva-F (ab') 2 Biodistribution experiments were performed 4, 12, 24, 48 and 72 hours later. Mice were sacrificed after blood sampling with the removal of the eyeball under anesthesia, and the radioactivity of each organ or tissue was expressed as% ID/g after weighing and counting the extracted tissues and organs for major tissue organs (heart, lung, liver, spleen, stomach, intestine, kidney, brain, muscle, tumor), and the results are shown in table 1 and fig. 7.
As can be seen from Table 1 and FIG. 7, for 124 I-HPP-Durva-F(ab') 2 The tumor reached a peak of about 1.57% ID/g 12 hours after injection, after which still an equivalent radioactivity was maintained. In normal organ tissues, blood has the highest activity level and gradually decreases with time, indicating that the nuclide molecular probe has good blood stability. In addition to blood, the liver and kidney have the highest radioactive uptake in many organ organs, suggesting that the nuclide molecular probe is metabolized in the liver and excreted from the kidney. At 48 hours the contrast of the tumor was evident, except for the faint liver and bladder shadows, only bright tumor uptake was visible on the image.
TABLE 1-72 hours 124 I-HPP-Durva-F(ab') 2 Biodistribution change table (% ID/g)
| |
4 |
12 hours | 24 hours | 48 hours | 72 hours |
| Blood circulation | 5.44 | 2.49 | 0.6 | 0.21 | 0.16 |
| Heart with heart-shaped | 0.72 | 0.35 | 0.05 | 0.11 | 0.05 |
| Lung (lung) | 0.77 | 0.2 | 0.04 | 0.14 | 0.12 |
| Liver disease | 2.68 | 2.01 | 0.94 | 0.44 | 0.38 |
| Stomach (stomach) | 0.51 | 0.31 | 0.08 | 0.07 | 0.04 |
| Sausage | 0.5 | 0.5 | 0.06 | -0.02 | 0.04 |
| Spleen | 1.26 | 1.05 | 0.45 | 0.21 | 0.17 |
| Kidney (Kidney) | 3.81 | 2.05 | 0.74 | 0.37 | 0.32 |
| Muscle | 0.23 | 0.21 | 0.07 | 0.02 | 0.03 |
| Brain | 0.18 | 0.11 | -0.02 | 0.07 | 0.01 |
| Tumor(s) | 1.25 | 1.57 | 1.21 | 1.11 | 0.95 |
Example 4
124 I-HPP-Durva-F(ab') 2 PET imaging in tumor-bearing mice:
for tumor bearing mice, tail vein injection of 1.11MBq 124 I-HPP-Durva-F(ab') 2 And then PET imaging is carried out according to a preset time point, and the abdominal cavity anesthesia is carried out on the mouse 5 minutes before imaging. During imaging, a mouse positioning image is firstly acquired, the original PET image acquisition is carried out after the position is ensured to be accurate, and the acquired image is exported after being processed by airborne software Inveon Research Workspace. The PET imaging result at 48h is shown in FIG. 8.
The above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way and substantially, it should be noted that those skilled in the art may make several modifications and additions without departing from the scope of the present invention, which should also be construed as a protection scope of the present invention.
Claims (6)
1. A labeled precursor of a PET imaging agent targeting PD-L1, characterized in that it is Durva-F (ab') 2 The antibody fragment is obtained by modifying acylating agent 3- (4-hydroxyphenyl) propionic acid-N succinamide ester, and the structural formula is shown in formula I, wherein, durva-F (ab') 2 The light chain amino acid sequence of the antibody fragment is shown as SEQ ID NO:1, and the heavy chain amino acid sequence is shown as SEQ ID NO:2, the acylation group SHPP is modified in Durva-F (ab') 2 Free amino groups at one or more lysine sites of the light chain and/or heavy chain of the antibody fragment,
2. a PET imaging agent targeting PD-L1, which is obtained by passing the labeled precursor according to claim 1 124 I is obtained after radioactive chemical labeling, wherein 124 I is marked on the ortho-position of benzene ring hydroxyl on acylation group and/or tyrosine, wherein, one ortho-position of the benzene ring hydroxyl is marked with 124 I or both ortho-positions are simultaneously marked with 124 I。
3. Use of a labeled precursor of a PD-L1-targeted PET imaging agent according to claim 1 for the preparation of a diagnostic agent/drug, and/or a therapeutic drug for labeling a diagnostic radionuclide and/or a therapeutic radionuclide.
4. The method for preparing a PD-L1-targeted PET imaging agent of claim 2, comprising:
step 1: the Dewaruzumab Durvalumab is subjected to enzyme digestion to remove Fc fragment, and the antibody fragment Durva-F (ab') with the target function is obtained after purification 2 ；
Step 2: amidating the antibody fragment with acylating agent 3- (4-hydroxyphenyl) propionic acid-N-succinamide ester, purifying to obtain modified product SHPP-Durva-F (ab') 2 ；
And step 3: subjecting the modified product obtained above to 124 I radiolabeling, purifying to obtain 124 I-HPP-Durva-F(ab') 2 Polypeptide molecular probes.
5. Use of the PD-L1-targeted PET imaging agent of claim 2 in the preparation of diagnostic agents/drugs, and/or therapeutic drugs for PD-L1-high expressing tumors, wherein said tumors comprise primary tumors or metastatic tumors.
6. The use of the PD-L1-targeting PET imaging agent of claim 2 in the preparation of a diagnosis and treatment kit for PD-L1 high-expression tumors.
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