Name: development of a 68gallium-labeled d-peptide pet tracer for imaging programmed death-ligand 1 expression
Uploaded: 2023-02-03T14:30:00
Description: Watch this Scientific Journal Video about Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression at JoVE.com

This study was supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (no. 2022-RC350-04) and the CAMS Innovation Fund for Medical Sciences (nos. 2021-I2M-1-026, 2022-I2M-1-026-1, 02120101, 02130101, and 2022-I2M-2-002).

The animal experimental procedures were approved by the Animal Ethics Committee of Nanjing Medical University or the National Institutes of Quantum Science and Technology. Mice experiments were strictly performed in compliance with the institutional guidelines of the Committee for the Care and Use of Laboratory Animals.
1. Peptide synthesis
<ol>
	<li>Swell 100 mg of 4-methylbenzhydrylamine (MBHA) resin (loading capacity of 0.37 mmol/g) in 1 mL of&#160;N-methyl-2-pyr...

The critical steps described in this method include the efficient labeling of 68Ga to DPA and choosing a suitable time window for PET imaging, which must perfectly match the pharmacodynamic pattern of DPA in the tumor.
In contrast to IHC, PET imaging enables real-time detection of whole-body PD-L1 expression in a noninvasive manner, allowing the visualization of each positive area in a heterogeneous tumor6,7. Peptides were c...

The discovery of immune checkpoint proteins was a breakthrough in tumor therapy, and has led to major advances in the development of immune checkpoint blockade therapy1. Programmed cell death-protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are potential drug targets with several antibodies approved by the Food and Drug Administration (FDA). PD-1 is expressed by tumor-infiltrating immune cells, such as CD4+, CD8+ T cells, and regulatory T cells. PD-L1 is one of the PD-1 ligands, which is overexpressed in a variety of tumor cells2,3. The interaction between PD-1 and PD-L1 inactivates PD-1, thus suppressing the antitumor immune response4. These findings suggest that the inhibition of PD-L1 can improve the killing effect of immune cells and eliminate tumor cells5. Currently, chromogenic immunohistochemistry (IHC) is the most commonly used approach to identify patients who are most likely to respond to immune checkpoint therapy6,7. However, due to the heterogeneous expression of PD-L1 in tumor cells, IHC results from biopsies cannot provide accurate information about PD-L1 expression in patients8. Previous studies have reported that only 20%-40% of patients gain long-term benefits from immune checkpoint blockade therapy1,9,10. There is, therefore, an urgent need to develop a new method to circumvent the false-negative results caused by the heterogeneous expression of these immune checkpoint proteins.
Molecular imaging technology, such as positron emission tomography (PET), enables real-time visualization of the whole body in a noninvasive way, and thus can outperform the conventional IHC method11,12,13. Radiolabeled antibodies, peptides, and small molecules are promising tracers for monitoring PD-L1 expression in cancer patients14,15,16,17,18,19,20,21,22,23,24,25. The FDA has approved three PD-L1 therapeutic monoclonal antibodies: avelumab, atezolizumab, and durvalumab26. Immuno-PET tracers based on these antibodies have been well documented27,28,29,30,31,32. Early-phase clinical trials have revealed limited value for clinical application, because of the unfavorable pharmacokinetics30. Compared with antibodies, peptides exhibit faster blood and organ clearance from healthy organs, and can be easily chemically modified33. Multiple peptides with high affinities for PD-1/PD-L1 have been reported2; WL12 is a reported peptide that shows specific binding to PD-L134. Radiolabeled tracers, [64Cu]WL12, [68Ga]WL12, and [18F]FPyWL12, have been reported to show high in vivo specific tumor-targeting ability, which allows for the harvest of high-quality images of PD-L1 expression in tumors26,35,36,37. Moreover, the first in-human evaluation of radiolabeled WL12 has demonstrated that [68Ga]WL12 (chelated by NOTA) has a safe and efficient potential for clinical tumor imaging38. Due to its high hydrophobicity and high uptake in the healthy liver, WL12 has limited clinical use. Other radiolabeling peptides, such as TPP1 and SETSKSF, which specifically bind to PD-L1, have also showed potential stability and specificity to visualize whole-body PD-L1 expression39,40. However, unmodified peptides are easily degraded by proteases, and are rapidly metabolized by the kidney. Dextrorotary(D)-peptides have been widely used as effective mediators, due to the poor stability of left-handed (L)-peptides41,42,43. D-peptides are hyper-resistant to proteolytic degradation and have remarkably prolonged metabolic half-lives. Compared with their L-counterparts, D-peptides mostly show specific binding abilities44,45,46.
This study designed a new method to detect PD-L1 expression, based on PET imaging of a 68Ga-labeled PD-L1-targeted D-peptide, D-dodecapeptide antagonist (DPA), in a tumor-bearing mouse model47. The stability of [68Ga]DPA was first studied in phosphate-buffered saline (PBS) and mouse serum, after which the binding affinity of [68Ga]DPA in PD-L1-overexpressing tumors was tested. Thereafter, PET imaging was performed in glioblastoma xenograft models to confirm whether [68Ga]DPA was an ideal PET tracer to monitor PD-L1 expression in tumors. The combination of PET imaging and DPA not only provides a new approach to overcome challenges associated with the heterogeneous expression of PD-L1, but also lays the basis for the development of D-peptide-based radiotracers.

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	<tbody>
		<tr>
			<td>1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)</td>
			<td>Merck</td>
			<td>60239-18-1</td>
			<td>68Ga&#160; chelation</td>
		</tr>
		<tr>
			<td>3,3-diaminobenzidine (DAB) Kit</td>
			<td>Sigma-Aldrich</td>
			<td>D7304-1SET</td>
			<td>Immunohistochemistry</td>
		</tr>
		<tr>
			<td>anti-PD-L1 monoclonal antibody</td>
			<td>Wuhan Proteintech</td>
			<td>17952-1-ap</td>
			<td>Immunohistochemistry: primary antibody</td>
		</tr>
		<tr>
			<td>BMS202</td>
			<td>Selleck</td>
			<td>1675203-84-5</td>
			<td>Competitive binding assay: inhibitor</td>
		</tr>
		<tr>
			<td>BSA</td>
			<td>Merck</td>
			<td>V900933</td>
			<td>Immunofluorescent : blocking&#160;</td>
		</tr>
		<tr>
			<td>DAPI</td>
			<td>Merck</td>
			<td>D9542</td>
			<td>Immunofluorescent: staining of nucleus</td>
		</tr>
		<tr>
			<td>Dichloromethane (DCM)</td>
			<td>Merck</td>
			<td>34856</td>
			<td>Solvent</td>
		</tr>
		<tr>
			<td>DIPEA</td>
			<td>Merck</td>
			<td>3439</td>
			<td>Peptide coupling</td>
		</tr>
		<tr>
			<td>EDC&#183;HCl</td>
			<td>Merck</td>
			<td>E6383</td>
			<td>Activation of DOTA</td>
		</tr>
		<tr>
			<td>FBS</td>
			<td>Gibco</td>
			<td>10099</td>
			<td>Cell culture: supplement</td>
		</tr>
		<tr>
			<td>FITC-conjugated anti-human IgG Fc Antibody</td>
			<td>Biolegend</td>
			<td>409310</td>
			<td>Immunofluorescent: secondary antibody</td>
		</tr>
		<tr>
			<td>FITC-conjugated anti PD-L1 antibody</td>
			<td>Biolegend</td>
			<td>393606</td>
			<td>Flow cytometry: direct antibody</td>
		</tr>
		<tr>
			<td>HCTU</td>
			<td>Energy Chemical</td>
			<td>E070004-25g</td>
			<td>Peptide coupling</td>
		</tr>
		<tr>
			<td>HRP labeled goat anti-rabbit antibody</td>
			<td>Servicebio</td>
			<td>GB23303</td>
			<td>Immunohistochemistry: secondary antibody</td>
		</tr>
		<tr>
			<td>Hydroxysuccinimide (NHS)</td>
			<td>Merck</td>
			<td>130672</td>
			<td>Activation of DOTA</td>
		</tr>
		<tr>
			<td>MeCN</td>
			<td>Merck</td>
			<td>PHR1551</td>
			<td>Solvent</td>
		</tr>
		<tr>
			<td>Morpholine</td>
			<td>Merck</td>
			<td>8.06127</td>
			<td>Fmoc- deprotection</td>
		</tr>
		<tr>
			<td>NMP</td>
			<td>Merck</td>
			<td>8.06072</td>
			<td>Solevent</td>
		</tr>
		<tr>
			<td>Paraformaldehyde</td>
			<td>Merck</td>
			<td>30525-89-4</td>
			<td>Fixation of tissues</td>
		</tr>
		<tr>
			<td>PBS</td>
			<td>Gibco</td>
			<td>10010023</td>
			<td>Cell culture: buffer</td>
		</tr>
		<tr>
			<td>Penicillin-streptomycin&#160;</td>
			<td>Gibco</td>
			<td>10378016</td>
			<td>Cell culture: supplement</td>
		</tr>
		<tr>
			<td>RIA tube</td>
			<td>PolyLab</td>
			<td>P10301A</td>
			<td>As tissue sample container</td>
		</tr>
		<tr>
			<td>RPMI-1640 medium</td>
			<td>Gibco</td>
			<td>11875093</td>
			<td>Cell culture: basic medium</td>
		</tr>
		<tr>
			<td>Sodium acetate</td>
			<td>Merck</td>
			<td>1.06264</td>
			<td>Salt for buffer</td>
		</tr>
		<tr>
			<td>Trypsin-EDTA</td>
			<td>Gibco</td>
			<td>25200056</td>
			<td>Cell culture: dissociation agent</td>
		</tr>
		<tr>
			<td>U87MG cell line</td>
			<td>Procell Life Science &#38; Technology Co</td>
			<td>CL-0238</td>
			<td>Cell model</td>
		</tr>
		<tr>
			<td>Equipment</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>68Ge/68Ga generator</td>
			<td>Isotope Technologies Munich, ITM</td>
			<td>Not applicable</td>
			<td>Generation of [68Ga]</td>
		</tr>
		<tr>
			<td>Autogamma counter</td>
			<td>Perkin Elmer&#160;</td>
			<td>Wizard2</td>
			<td>Detection of radioactivity</td>
		</tr>
		<tr>
			<td>Confocal fluorescent microscopy</td>
			<td>Keyence</td>
			<td></td>
			<td>Observation of immunofluorescent results</td>
		</tr>
		<tr>
			<td>Flow cytometer</td>
			<td>Becton Dickinson, BD</td>
			<td>LSRII</td>
			<td>Monitoring the PD-L1 positive cells</td>
		</tr>
		<tr>
			<td>High-performance liquid chromatography (HPLC)</td>
			<td>SHIMAZU</td>
			<td>LC-20AT&#160;</td>
			<td>Purification of DPA peptide</td>
		</tr>
		<tr>
			<td>PET scanner</td>
			<td>Siemens Medical Solutions</td>
			<td>Inveon MultiModality System</td>
			<td>PET imaging</td>
		</tr>
		<tr>
			<td>Optical microscopy</td>
			<td>Nikon&#160;</td>
			<td>Eclipse E100</td>
			<td>Observation of immunohistochemistry results</td>
		</tr>
		<tr>
			<td>Solid phase peptide synthesizer</td>
			<td>Promega Vac-Man Laboratory Vacuum Manifold</td>
			<td>LOT#11101</td>
			<td>Synthesis of DPA-DOTA peptide</td>
		</tr>
		<tr>
			<td>Software</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>ASIPro</td>
			<td>Siemens Medical Solutions</td>
			<td>Not applicable</td>
			<td>Analysis of PET-CT results</td>
		</tr>
		<tr>
			<td>FlowJo</td>
			<td>Becton Dickinson, BD</td>
			<td>FlowJo 7.6.1</td>
			<td>Analysis of the flow cytometer results</td>
		</tr>
		<tr>
			<td>Inveon Acquisition Workplace (IAW)</td>
			<td>Siemens Medical Solutions</td>
			<td>Not applicable</td>
			<td>Management of PET mechine</td>
		</tr>
		<tr>
			<td>Prism</td>
			<td>Graphpad</td>
			<td>Prism 8.0</td>
			<td>Analysis of the data&#160;</td>
		</tr>
	</tbody>
</table>

development of a 68gallium-labeled d-peptide pet tracer for imaging programmed death-ligand 1 expression

The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized cancer therapies in recent years. However, only a fraction of patients responds to PD-1/PD-L1 inhibitors, owing to the heterogeneous expression of PD-L1 in tumor cells. This heterogeneity presents a challenge in the precise detection of tumor cells by the commonly used immunohistochemistry (IHC) approach. This situation calls for better methods to stratify patients who will benefit from immune checkpoint blockade therapy, to improve treatment efficacy. Positron emission tomography (PET) enables real-time visualization of the whole-body PD-L1 expression in a noninvasive way. Therefore, there is a need for the development of radiolabeled tracers to detect PD-L1 distribution in tumors through PET imaging.
Compared to their L-counterparts, dextrorotary (D)-peptides have properties such as proteolytic resistance and remarkably prolonged metabolic half-lives. This study designed a new method to detect PD-L1 expression based on PET imaging of 68Ga-labeled PD-L1-targeted D-peptide, a D-dodecapeptide antagonist (DPA), in tumor-bearing mice. The results showed that the [68Ga]DPA can specifically bind to PD-L1-overexpressing tumors in vivo, and showed favorable stability as well as excellent imaging ability, suggesting that [68Ga]DPA-PET is a promising approach for the assessment of PD-L1 status in tumors.

[68Ga]DPA radiolabeling and stability 
The model peptide, DPA, is an effective PD-L1 antagonist. DOTA-DPA was obtained with &#62;95% purity and a yield of 68%. The mass of DOTA-DPA is experimentally observed at 1,073.3 ([M+2H]2+). 68Gallium is considered a suitable radionuclide to label peptides for PET imaging, and therefore was chosen for this study. To radiolabel DPA with 68Ga (half-life: 68 min), DOTA-PEG3-DPA was synt...

Watch this Scientific Journal Video about Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression at JoVE.com

Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

This study developed a noninvasive and real-time method to evaluate the distribution of programmed death-ligand 1 in the whole body, based on positron emission tomographic imaging of [68Ga] D-dodecapeptide antagonist. This technique has advantages over conventional immunohistochemistry and improves the efficiency of identifying appropriate patients who will benefit from immune checkpoint blockade therapy.

Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression

The development of immune checkpoint blockade therapy based on programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has revolutionized ...

Denne metode bruger D-peptid DPA, mærket med Gallium-68. Radiosporstoffet Gallium-68 til mærkning af DPA muliggør visualisering i realtid af PDL-1-ekspression i hele kroppen på en ikke-invasiv måde. Anvendelsen af D-peptid giver radiosporstoffet hyperresistent over for proteolytisk nedbrydning og forlænger deres metaboliske halveringstider bemærkelsesværdigt.Især kan teknikken anvendes til at evaluere forskellige sygdomme, der udsættes for opdagelsen af specifikke mål og udviklingen af radiosporere med god telefonopkaldskinetik. Teknikken kan også anvendes til behandling af PDL-1-positive tumorer, mens DPA mærkes med andre radionukleotider, såsom Lutetium-177 og Actinium-225. Demonstration af proceduren vil være Wu Jiang, en forsker fra mit laboratorium.Til radioaktiv mærkning af peptidet d-dodecapeptidantagonist eller DPA pipetteres fem mikroliter af den fremstillede stambuffer indeholdende DPA i en 1,5 ml polypropylenbeholder med en skruehætte og tilsættes 400 mikroliter 68 galliumtrichlorid til beholderen. Vortex blandingen i fem sekunder. Mål blandingens pH ved hjælp af pH-teststrimler, og juster pH til 4 til 4,5 med 0,1 molært natriumhydroxid.Inkuber opløsningen ved stuetemperatur i fem til 10 minutter. Følg derefter betingelserne nævnt i teksten, underkast reaktionsblandingen til radio HPLC til analyse af radiomærkningsudbyttet. For at teste sporstofstabiliteten i PBS tilsættes 10 mikroliter Gallium-68-mærket DPA i natriumacetatopløsning til 990 mikroliter PBS.Inkuber blandingen ved 37 grader Celsius i en, to og fire timer med let omrøring. Saml 200 mikroliter af opløsningen på hvert tidspunkt og analyser det via radio HPLC. For at teste sporstofstabiliteten i museserum tilsættes 10 mikroliter Gallium-68-mærket DPA i natriumacetatopløsning til 90 mikroliter af det frisklavede museserum og inkuberer blandingen ved 37 grader Celsius i en, to og fire timer med let omrøring.Derefter samles 20 mikroliter af opløsningen på hvert nævnte tidspunkt og tilsættes 100 mikroliter aceto nitrilvandblanding i den opsamlede delprøve. Centrifuger blandingen ved 5.000 G i 10 minutter ved 25 grader Celsius. Supernatanten analyseres ved hjælp af radio-HPLC.Dyrk U-87 MG-cellerne i plader med 12 brønde, indtil 80% sammenløb er nået. Fjern derefter mediet og vask cellerne med 0,5 ml PBS. Fortynd Gallium-68-mærket DPA i frisk medium til en koncentration på 74 kilobecquerel pr. Milliliter.Derefter tilsættes 0,5 ml af den fortyndede Gallium-68-mærkede DPA-buffer til hver brønd. Inkuber cellerne med Gallium-68-mærket DPA ved 37 grader Celsius i varigheder på 10, 30, 40 og 120 minutter. Efter inkubation aspireres mediet ved hjælp af en pipette og vaskes cellerne med 0,5 ml PBS tre gange.Derefter tilsættes 300 mikroliter 0,5 molær natriumhydroxidopløsning pr. Brønd for at lyse cellerne. Efter 30 sekunder samles de viskøse cellelysater i 1,5 ml rør. Pladen vaskes ved at tilsætte 0,4 ml PBS pr. brønd to gange, og vaskeopløsningen opsamles i de nævnte 1,5 ml rør.Start den indbyggede computer i den automatiske gammatæller, og sæt rørene i den indbyggede hylde. Når du har lagt alle prøverne på transportøren, skal du trykke på startknappen. Resultaterne beregnes i den interne software, mens udlæsningen registrerer henfaldskorrelerede tællinger pr. minut eller CPM for hvert rør.Saml U-87 MG-cellerne efter protokollen nævnt i teksten og aspirer cellerne til en 0,5 ml sprøjte. Tag derefter BALB / c Nøgne mus og injicer cellerne subkutant og opretholder et antal på to tumorer pr. Mus. Overvåg tumorvækst efter injektion, indtil tumorvolumenet er 100 til 300 kubikmillimeter.For at udføre PET-billeddannelse injiceres sporstoffer intravenøst gennem et forudinstalleret halevenekateter. Opret en scanningsarbejdsgang på en værtscomputer ved hjælp af referencesoftwaren, efterfulgt af oprettelse af en studiemappe og indstilling af anskaffelsesprotokollen i henhold til producentens retningslinjer. Udfør dynamiske scanninger på hver mus i 60 minutter i 3D-listetilstand.Definer derefter en histogramprotokol og en rekonstruktionsprotokol efter producentens anvisninger. Brug Hannings filter med en Nyquist-afskæring på 0,5 cyklusser pr. pixel til at rekonstruere dynamiske PET-billeder i 25 til 30 minutter og 55 til 60 minutter gennem filtreret tilbageprojektion. Generer maksimal intensitetsprojektion eller MIP-billeder for alle mus.Administrer Gallium-68-mærket DPA til U-87 MG bærende BALB / c Nøgne mus gennem haleveneinjektion. Efter eutanasi dissekeres dyrets brystvæg og åbner hjertet. Brug en milliliter sprøjte til at trække blod og klemme blodet fra sprøjten ind i et radioimmunoassayrør eller RIA, der måler 13 millimeter i diameter til gammatælleren.Punktafgifter de vigtigste organer og tumorer og placere dem i lignende RIA-rør til gammatælleren. Væg alle de vigtigste organer, der er nævnt i teksten. Mål radioaktiviteten i de indsamlede organer ved hjælp af en automatisk gammatæller og henfald korriger værdierne.Beregn procentdelen af injiceret dosis pr. gram vådt væv. Den Gallium-68-mærkede DPA viste høj radiokemisk udbytteurenhed. Det var meget stabilt i både PBS og museserum og viste ingen gallium-68-nedbrydning eller peptidhydrolyse efter fire timers inkubation.Ca. 60% af U-87 MG-cellerne viste sig at være programmeret til dødsligand en eller PDL-1-positiv ved flowcytometri, og immunofluorescerende farvning bekræftede stærk ekspression af PDL-1 i U-87 MG-cellerne. U-87 MG-celler viste en tidsafhængig optagelse af Gallium-68-mærket DPA, hvilket reducerede signifikant ved anvendelse af en PDL-1-hæmmer, BMS-202, som blokeringsmiddel. Den estimerede bindingsaffinitet for BMS-202 var 43,8 nanomol pr. Liter, da Gallium-68-mærket DPA blev brugt som konkurrent.Hele kroppen PET-billeder afslørede høj Gallium-68-mærket DPA-akkumulering i tumoren efter 30 og 60 minutters injektion. Et parallelt eksperiment viste lidt Gallium-68-mærket DPA-akkumulering i de negative kontrol Bon-1-tumorer 60 minutter efter injektion. Endvidere afslørede immunohistokemisk farvning, at U-87 MG-cellerne præsenterede betydelig PDL-1-ekspression, men ikke Bon-1-tumoren.Hæmatoxylin og eosinfarvning viste en lignende cellemorfologi mellem de to tumorvæv. Ex-vivo biodistributionsundersøgelsen viste hurtig clearance af radioaktivitet og blod i de fleste analyserede organer, herunder hjerte, lever, lunge og muskel. Nyren akkumulerede den højeste mængde radioaktivitet, mens tumoren udviste den næsthøjeste sporoptagelse på alle tidspunkter.Strukturen af D-peptid er anderledes ved hjælp af en effektiv metode til mærkning af DPA med Gallium-68 er det vigtigste skridt. Denne teknik banede vejen for at udnytte PET-testen som effektive radioaktive lægemidler til håndtering af forskellige kræftformer, både som PET-sporstoffer og radiodiagnostiske midler.

Research

JoVE Journal

Cancer Research

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A Practical Guide for the Production and PET/CT Imaging of 68Ga-DOTATATE for Neuroendocrine Tumors in Daily Clinical Practice

A Practical Guide for the Production and PET/CT Imaging of 68Ga-DOTATATE for Neuroendocrine Tumors in Daily Clinical Practice

En praktisk vejledning for produktion og PET/CT billeddannelse af 68Ga-DOTATATE for Neuroendokrine tumorer i daglig klinisk praksis

Neuroendocrine tumors are a rare form of cancer that arise from neuroendocrine cells and can be present at almost any location throughout the body. ...