FIGURE 1 - uploaded by Paul Morin
Content may be subject to copyright.
Synthesis of 18 F-BMT-187144. Reagents and conditions: a) NaN 3 , ethanol 90°C 17 h; b) NaH, 2-nitropyridin-3-ol 0-60°C, 4 h; c) K.2.2.2 K 18 F, dimethyl sulfoxide 120°C 10 min.
Source publication
The programmed death protein (PD-1) and its ligand (PD-L1) play critical roles in a checkpoint pathway cancer cells exploit to evade the immune system. A same-day PET imaging agent for measuring PD-L1 status in primary and metastatic lesions could be important for optimizing drug therapy. Herein, we have evaluated the tumor targeting of an anti-PD-...
Contexts in source publication
Context 1
... were made to use previously described prosthetic groups to label the adnectin platform with 18 F, including the azide containing 1-azido-2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)ethane (31). Un- fortunately, this approach did not yield the desired product. Un- der dilute reaction conditions needed to keep the total volume of ethanol in the reaction solution below 10% (for adnectin stabil- ity) no 18 F labeling occurred. Attempts to concentrate the crude reaction solution led to ethanol concentrations above 10%, which led to aggregation of the adnectin. Further attempts to concen- trate this prosthetic group in solution volatilized the product. To solve this issue, a nitropyridine was incorporated (Fig. 1), which allowed for rapid 18 F incorporation into the molecule and pro- vided a nonvolatile prosthetic group. This allowed for the com- plete removal of organic solvents with minimal radioactivity loss (Supplemental Table 4). The product could then be reconstituted in aqueous buffer for stability of the adnectin. The novel labeled prosthetic group was stable in this buffer system for over an hour (Supplemental Fig. 5) and enabled efficient 18 F labeling of the PD-L1 ...
Context 2
... 18 F-labeled derivative of ADX_5322_A02 anti-PD-L1 adnectin was synthesized using a 18 F prosthetic group, 18 F- BMT-187144 ( Fig. 1). 18 F-BMT-187144 was generated in high radiochemical yield (.70% non-decay-corrected yield, n 5 40), in greater than 90% radiochemical purity, was stable in a PBS solution over 1 h, and was reduced to dryness without loss of radioactivity, enabling efficient protein labeling with 18 F (supplemental materials). The 18 F-BMT-187144 prosthetic group was then used to synthesize 18 F-BMS-986192 as shown in Figure 2, using copper-free click chemistry. 18 F-BMS-986192 (1.1 6 0.3 GBq [n 5 15]) was isolated, starting from 29.6 GBq of 18 F-fluoride with 96% 6 3% radiochem- ical purity and a specific activity of 63 6 3 ...
Context 3
... F-fluoride (29.6 GBq) was transferred through a preconditioned anion exchange cartridge and eluted with potassium carbonate (3 mg) and 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (15 mg) in 1.4 mL of acetonitrile. The solvent was azeotroprically dried, and to this mixture was added 3-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy) ethoxy)-2-nitropyridine (2 mg) in 0.5 mL of dimethyl sulfoxide. This solution was heated at 120°C for 10 min, followed by dilution with 3 mL of water and transferred onto a Luna C18 (250 · 10 mm) high- performance liquid chromatography column. The prosthetic group 18 F-BMT-187144 was purified using a mobile phase mixture of 32% acetonitrile in 0.1% trifluoroacetic acid at a flow rate of 4.6 mL/min. 18 F-BMT-187144 was collected into a 100-mL flask that contained 25 mL of water, and its contents were delivered to a C18 cartridge. 18 F-BMT-187144 was released from the cartridge with 3 mL of eth- anol, evaporated to dryness, and reconstituted into 0.1 mL of sterile water. To this solution was added 0.2 mL of ADX_5322_A02- DBCO (3 mg/mL) in phosphate-buffered saline (PBS). The reaction mixture was gently mixed for 45 min at 45°C. 18 F-BMS-986192 was purified using a Superdex 200 10/300 GL size-exclusion column and 1· PBS mobile phase at a 0.5 mL/min flow rate. 18 F-BMS-986192 was isolated over a 5-min period and passed through a 0.2-mm polyethersulfone membrane filter and into a sterile vial as the final formulated product. The radiochemical purity was determined using a high-performance liquid chromatography (Agilent) system and a Posi-Ram (INUS) radio-high-performance liquid chromatography detector. Methods for quality control and specific activity of 18 F- BMS-986192 are found in the supplemental materials (Supplemen- tal Figs. ...
Context 4
... vial as the final formulated product. The radiochemical purity was determined using a high-performance liquid chromatography (Agilent) system and a Posi-Ram (INUS) radio-high-performance liquid chromatography detector. Methods for quality control and specific activity of 18 F- BMS-986192 are found in the supplemental materials (Supplemen- tal Figs. ...
Context 5
... 18 F-labeled derivative of ADX_5322_A02 anti-PD-L1 adnectin was synthesized using a 18 F prosthetic group, 18 F- BMT-187144 ( Fig. 1). 18 F-BMT-187144 was generated in high radiochemical yield (.70% non-decay-corrected yield, n 5 40), in greater than 90% radiochemical purity, was stable in a PBS solution over 1 h, and was reduced to dryness without loss of radioactivity, enabling efficient protein labeling with 18 F (supplemental materials). The 18 F-BMT-187144 ...
Context 6
... below 10% (for adnectin stabil- ity) no 18 F labeling occurred. Attempts to concentrate the crude reaction solution led to ethanol concentrations above 10%, which led to aggregation of the adnectin. Further attempts to concen- trate this prosthetic group in solution volatilized the product. To solve this issue, a nitropyridine was incorporated (Fig. 1), which allowed for rapid 18 F incorporation into the molecule and pro- vided a nonvolatile prosthetic group. This allowed for the com- plete removal of organic solvents with minimal radioactivity loss (Supplemental Table 4). The product could then be reconstituted in aqueous buffer for stability of the adnectin. The novel labeled ...
Similar publications
![Figure 1 [ 89 Zr]Zr-N-suc-Df-ERY974 distribution in time. (A) Maximal...](publication/340221552/figure/fig1/AS:873885981483008@1585362062562/89-ZrZr-N-suc-Df-ERY974-distribution-in-time-A-Maximal-intensity-projection-images_Q320.jpg)
![Figure 2 [ 89 Zr]Zr-N-suc-Df-ERY974 distribution in immunodeficient NOG...](publication/340221552/figure/fig2/AS:873885985677313@1585362063064/89-ZrZr-N-suc-Df-ERY974-distribution-in-immunodeficient-NOG-mice-bearing-different_Q320.jpg)
![Figure 3 Distribution of [ 89 Zr]Zr-N-suc-Df-ERY974 and control tracers...](publication/340221552/figure/fig3/AS:873885985689600@1585362063115/Distribution-of-89-ZrZr-N-suc-Df-ERY974-and-control-tracers-in-HepG2-xenograft-bearing_Q320.jpg)
![Figure 5 Intratumoral distribution of [ 89 Zr]Zr-N-suc-Df-ERY974 in...](publication/340221552/figure/fig4/AS:873885985669121@1585362063482/ntratumoral-distribution-of-89-ZrZr-N-suc-Df-ERY974-in-HepG2-bearing-huNOG-mice-A_Q320.jpg)
Background
Bispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibo...
The acidic microenvironment of tumor tissues has been proven to be a major characteristic for differentiation from normal tissues, thereby providing a desirable target for both disease diagnosis and functional imaging. We herein introduce a way to endow gold nanoparticles with aggregation behaviour induced by pH tuning. Nanoparticle surface was mod...
PhotoAcoustic Imaging (PAI) is a biomedical imaging modality currently under evaluation in preclinical and clinical settings. In this work, ICG is coupled to an integrin binding vector (ICG-RGD) to combine the good photoacoustic properties of ICG and the favourable αvβ3-binding capabilities of a small RGD cyclic peptidomimetic. ICG-RGD is character...
Background:
Specific targeting ability and good cell penetration are two critical requirements of tumor-targeted delivery systems. In the present work, we developed a novel matrix metalloprotein-triggered, cell-penetrating, peptide-modified, star-shaped nanoparticle (NP) based on a functionalized copolymer (MePEG-Peptide-Tri-CL), with the peptide...
Introduction
Despite improvements in chemotherapy and molecularly targeted therapies, the life expectancy of patients with advanced non-small cell lung cancer (NSCLC) remains less than 1 year. There is thus a major global need to advance new treatment strategies that are more effective for NSCLC. Drug delivery using liposomal particles has shown su...
Citations
... This lack of consistency in findings underscores the absence of a singular biomarker capable of adequately stratifying patients, not only within the context of gastric cancer but also across other tumor types. Clinical and preclinical positron-emission tomography (PET) studies using radiolabeled anti-PD-L1 antibodies have successfully demonstrated non-invasive imaging of PD-L1 expression in tumors with potential for clinical response prediction to ICI (12)(13)(14)(15)(16). While PD-L1-targeting PET approaches hold the potential to provide valuable insights into the assessment of heterogeneity and PD-L1 status throughout the whole body and predict response to ICI, their applicability in the context of gastric cancer imaging remains uncertain. ...
Introduction
This study aimed to investigate the dynamics of programmed death-ligand 1 (PD-L1) expression, spatial heterogeneity, and binding affinity of FDA-approved anti-PD-L1 antibodies (avelumab and atezolizumab) in gastric cancer. Additionally, we determined how PD-L1 glycosylation impacts antibody accumulation in gastric cancer cells.
Methods
Dynamic PD-L1 expression was examined in NCIN87 gastric cancer cells. Comparative binding studies of avelumab and atezolizumab were conducted in gastric cancer models, both in vitro and in vivo. Antibody uptake in tumors was visualized through positron emission tomography (PET) imaging. PD-L1 glycosylation status was determined via Western blot analyses before and after PNGase F treatment.
Results
Consistent findings revealed time-dependent PD-L1 induction in NCIN87 gastric cancer cells and spatial heterogeneity in tumors, as shown by PET imaging and immunofluorescence. Avelumab displayed superior binding affinity to NCIN87 cells compared to atezolizumab, confirmed by in vivo PET imaging and ex vivo biodistribution analyses. Notably, PD-L1 glycosylation at approximately 50 kDa was observed, with PNGase F treatment inducing a shift to 35 kDa in molecular weight. Tissue samples from patient-derived xenografts (PDXs) validated the presence of both glycosylated and deglycosylated PD-L1 (degPD-L1) forms in gastric cancer. Immunofluorescence microscopy and binding assays demonstrated enhanced avelumab binding post-deglycosylation.
Discussion
This study provides an understanding of dynamic and spatially heterogeneous PD-L1 expression in gastric cancer. Anti-PD-L1 immunoPET was able to visualize gastric tumors, and PD-L1 glycosylation has significant implications for antibody recognition. These insights contribute to demonstrating the complexities of PD-L1 in gastric cancer, holding relevance for refining PD-L1 imaging-based approaches.
... This lack of consistency in findings underscores the absence of a singular biomarker capable of adequately stratifying patients, not only within the context of gastric cancer but also across other tumor types. Clinical and preclinical positron-emission tomography (PET) studies using radiolabeled anti-PD-L1 antibodies have successfully demonstrated non-invasive imaging of PD-L1 expression in tumors with potential for clinical response prediction to ICI (12)(13)(14)(15)(16). While PD-L1-targeting PET approaches hold the potential to provide valuable insights into the assessment of heterogeneity and PD-L1 status throughout the whole body and predict response to ICI, their applicability in the context of gastric cancer imaging remains uncertain. ...
This MIB guide briefly summarizes the generation of patient-derived xenografts (PDXs) and highlights the importance of validating PDX models for the presence of B cell lymphoma of human origin before their use in radiotheranostic applications. The use of this protocol will allow researchers to learn different methods for screening PDX models for Epstein-Barr virus (EBV)-infected B cell lymphoma.
... Frontiers in Pharmacology frontiersin.org 09 which rapid clearance is favored (Donnelly et al., 2018). The strong half-life prolonging effect of the ABD that we observed, might be due to three different, possibly interconnected mechanisms. ...
... Frontiers in Pharmacology frontiersin.org 11 strategies to increase tumor cell-selectivity of monobodies by fusion with FN3-based tumor-targeting moieties, that bind PD-L1 or EGFR (Hackel et al., 2012;Donnelly et al., 2018;Hantschel lab, unpublished results). Alternative binders to other cell-surface markers, such as DARPins for glutamate receptor subunit GluA4, the endothelial surface marker CD105, and the natural killer cell marker NKp46 were developed for gene-and cell-therapy approaches and can be used to target monobodies to specific cell types (Hartmann et al., 2018). ...
Cancer is a leading cause of death worldwide. Several targeted anticancer drugs entered clinical practice and improved survival of cancer patients with selected tumor types, but therapy resistance and metastatic disease remains a challenge. A major class of targeted anticancer drugs are therapeutic antibodies, but their use is limited to extracellular targets. Hence, alternative binding scaffolds have been investigated for intracellular use and better tumor tissue penetration. Among those, monobodies are small synthetic protein binders that were engineered to bind with high affinity and selectivity to central intracellular oncoproteins and inhibit their signaling. Despite their use as basic research tools, the potential of monobodies as protein therapeutics remains to be explored. In particular, the pharmacological properties of monobodies, including plasma stability, toxicity and pharmacokinetics have not been investigated. Here, we show that monobodies have high plasma stability, are well-tolerated in mice, but have a short half-life in vivo due to rapid renal clearance. Therefore, we engineered monobody fusions with an albumin-binding domain (ABD), which showed enhanced pharmacological properties without affecting their target binding: We found that ABD-monobody fusions display increased stability in mouse plasma. Most importantly, ABD-monobodies have a dramatically prolonged in vivo half-life and are not rapidly excreted by renal clearance, remaining in the blood significantly longer, while not accumulating in specific internal organs. Our results demonstrate the promise and versatility of monobodies to be developed into future therapeutics for cancer treatment. We anticipate that monobodies may be able to extend the spectrum of intracellular targets, resulting in a significant benefit to patient outcome.
... To date, a variety of radiotracers targeting PD-L1 or PD-1 have been developed (Krutzek et al. 2022). These include large and midsized constructs, such as antibodies (Heskamp et al. 2015;Kikuchi et al. 2017;Li et al. 2018;Jagoda et al. 2019), nanobodies (Broos et al. 2017;Bridoux et al. 2020), and adnectines (Donnelly et al. 2018;Stutvoet et al. 2020). Additionally, smaller structures like peptides (Kuan et al. 2019;Zhang et al. 2023) and small molecules (Miao et al. 2020;Maier et al. 2022;Xu et al. 2023) were described. ...
Background
Programmed cell death ligand 1 (PD-L1) plays a critical role in the tumor microenvironment and overexpression in several solid cancers has been reported. This was associated with a downregulation of the local immune response, specifically of T-cells. Immune checkpoint inhibitors showed a potential to break this localized immune paralysis, but only 30% of patients are considered responders. New diagnostic approaches are therefore needed to determine patient eligibility. Small molecule radiotracers targeting PD-L1, may serve as such diagnostic tools, addressing the heterogeneous PD-L1 expression between and within tumor lesions, thus aiding in therapy decisions.
Results
Four biphenyl-based small-molecule PD-L1 ligands were synthesized using a convergent synthetic route with a linear sequence of up to eleven steps. As a chelator NODA-GA, CB-TE2A or DiAmSar was used to allow radiolabeling with copper-64 ([⁶⁴Cu]Cu-14–[⁶⁴Cu]Cu-16). In addition, a dimeric structure based on DiAmSar was synthesized ([⁶⁴Cu]Cu-17). All four radioligands exhibited high proteolytic stability (> 95%) up to 48 h post-radiolabeling. Saturation binding yielded moderate affinities toward PD-L1, ranging from 100 to 265 nM. Real-time radioligand binding provided more promising KD values around 20 nM for [⁶⁴Cu]Cu-14 and [⁶⁴Cu]Cu-15. In vivo PET imaging in mice bearing both PC3 PD-L1 overexpressing and PD-L1-mock tumors was performed at 0–2, 4–5 and 24–25 h post injection (p.i.). This revealed considerably different pharmacokinetic profiles, depending on the substituted chelator. [⁶⁴Cu]Cu-14, substituted with NODA-GA, showed renal clearance with low liver uptake, whereas substitution with the cross-bridged cyclam chelator CB-TE2A resulted in a primarily hepatobiliary clearance. Notably, the monomeric DiAmSar radioligand [⁶⁴Cu]Cu-16 demonstrated a higher liver uptake than [⁶⁴Cu]Cu-15, but was still renally cleared as evidenced by the lack of uptake in gall bladder and intestines. The dimeric structure [⁶⁴Cu]Cu-17 showed extensive accumulation and trapping in the liver but was also cleared via the renal pathway. Of all tracer candidates and across all timepoints, [⁶⁴Cu]Cu-17 showed the highest accumulation at 24 h p.i. in the PD-L1-overexpressing tumor of all timepoints and all radiotracers, indicating drastically increased circulation time upon dimerization of two PD-L1 binding motifs.
Conclusions
This study shows that chelator choice significantly influences the pharmacokinetic profile of biphenyl-based small molecule PD-L1 radioligands. The NODA-GA-conjugated radioligand [⁶⁴Cu]Cu-14 exhibited favorable renal clearance; however, the limited uptake in tumors suggests the need for structural modifications to the binding motif for future PD-L1 radiotracers.
... Additionally, and perhaps more widely investigated at present, are agents targeting the PD-L1 co-receptor. Radiotracers built from 64 Cu-, 89 Zr-, 18 F-, 111 In-, and 99m Tc-containing scaffolds with high-affinity PD-L1-specific peptides are being used in pre-clinical studies to precisely define tumor surface protein expression [51][52][53][54][55]. Human studies are also underway, with a recent trial of 22 patients demonstrating that PD-L1-specific 89 Zr PET tracer uptake was more strongly correlated with outcomes than immunohistochemistry or RNA sequencingbased biomarkers [56]. ...
The integration of artificial intelligence (AI) and positron emission tomography (PET) imaging has the potential to become a powerful tool in drug discovery. This review aims to provide an overview of the current state of research and highlight the potential for this alliance to advance pharmaceutical innovation by accelerating the development and deployment of novel therapeutics. We previously performed a scoping review of three databases (Embase, MEDLINE, and CENTRAL), identifying 87 studies published between 2018 and 2022 relevant to medical imaging (e.g., CT, PET, MRI), immunotherapy, artificial intelligence, and radiomics. Herein, we reexamine the previously identified studies, performing a subgroup analysis on articles specifically utilizing AI and PET imaging for drug discovery purposes in immunotherapy-treated oncology patients. Of the 87 original studies identified, 15 met our updated search criteria. In these studies, radiomics features were primarily extracted from PET/CT images in combination (n = 9, 60.0%) rather than PET imaging alone (n = 6, 40.0%), and patient cohorts were mostly recruited retrospectively and from single institutions (n = 10, 66.7%). AI models were used primarily for prognostication (n = 6, 40.0%) or for assisting in tumor phenotyping (n = 4, 26.7%). About half of the studies stress-tested their models using validation sets (n = 4, 26.7%) or both validation sets and test sets (n = 4, 26.7%), while the remaining six studies (40.0%) either performed no validation at all or used less stringent methods such as cross-validation on the training set. Overall, the integration of AI and PET imaging represents a paradigm shift in drug discovery, offering new avenues for more efficient development of therapeutics. By leveraging AI algorithms and PET imaging analysis, researchers could gain deeper insights into disease mechanisms, identify new drug targets, or optimize treatment regimens. However, further research is needed to validate these findings and address challenges such as data standardization and algorithm robustness.
... Compared to IHC, PET imaging with radionuclide-labeled molecules has the advantage of providing a full-version and dynamic picture of the expression of markers in vivo. Both primary and metastatic tumors can be evaluated in a noninvasive manner [54,55]. ...
Background
Immune checkpoint inhibitors (ICIs) have made significant progress in oncotherapy improving survival of patients. However, the benefits are limited to only a small subgroup of patients who could achieve durable responses. Early prediction of response may enable treatment optimization and patient stratification. Therefore, developing appropriate biomarkers is critical to monitoring efficacy and assessing patient response to ICIs.
Main body
Herein, we first introduce a new potential biomarker, CD103, expressed on tissue-resident memory T cells, and discuss the potential application of CD103 PET imaging in predicting immune checkpoint inhibitor treatment. In addition, we describe the current targets of ImmunoPET and compare these targets with CD103. To assess the benefit of PET imaging, a comparative analysis between ImmunoPET and other imaging techniques commonly employed for tumor diagnosis was performed. Additionally, we compare ImmunoPET and immunohistochemistry (IHC), a widely utilized clinical method for biomarker identification with respect to visualizing the immune targets.
Conclusion
CD103 ImmunoPET is a promising method for determining tumor-infiltrating lymphocytes (TILs) load and response to ICIs, thereby addressing the lack of reliable biomarkers in cancer immunotherapy. Compared to general T cell markers, CD103 is a specific marker for tissue-resident memory T cells, which number increases during successful ICI therapy. ImmunoPET offers noninvasive, dynamic imaging of specific markers, complemented by detailed molecular information from immunohistochemistry (IHC). Radiomics can extract quantitative features from traditional imaging methods, while near-infrared fluorescence (NIRF) imaging aids tumor detection during surgery. In the era of precision medicine, combining such methods will offer a more comprehensive approach to cancer diagnosis and treatment.
... It has been demonstrated that radiolabeled PD-1 or PD-L1 antibodies can be used to non-invasively assess PD-1 or PD-L1 expression in NHPs, human tumor xenografts, and syngeneic tumor models [12][13][14][15][16][17]. Although radiolabeled antibodies are used for imaging tumor-specific proteins, a longer clearance time of radiolabeled antibodies is required for enhanced image contrast and lesion detection. ...
... In this regard, PD-L1 tracers with low molecular weight, faster clearance, short-lived radioactivity, that are relatively easy to radio-synthesize with high specific activity are desirable for clinical application due to the "same day" imaging feasibility and wider clinical availability. 18 F-BMS986192, an anti-PD-L1 adnectin derived from the 10th type III domain of human fibronectin (~ 10 kDa) was reported as the first PD-L1 PET tracer for same-day imaging and has been successfully translated into clinical study application [17,18]. However, its synthesis remains challenging and is isolated in modest yields. ...
... L2987 is a PD-L1 positive human lung adenocarcinoma cell line, while HT-29 is a PD-L1 negative human colorectal adenocarcinoma cell line (American Type Culture Collection) [17]. L2987 cells were cultured in Roswell Park Memorial Institute medium supplemented with 10% fetal bovine serum (FBS), while the HT-29 cells were cultured in Minimum Essentia Media supplemented with 10% FBS. ...
Purpose
In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an ¹⁸ F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients.
Procedures
¹⁸ F-BMS-986229 was characterized for PD-L1 expression assessment by autoradiography or PET imaging. ¹⁸ F-BMS-986229 was utilized to evaluate tumor PD-L1 target engagement in competition with a macrocyclic peptide inhibitor of PD-L1 (BMS-986189) over a range of doses using PET imaging. A whole-body radiation dosimetry study of ¹⁸ F-BMS-986229 in healthy non-human primates (NHPs) was performed.
Results
In vitro autoradiography showed an 8:1 binding ratio in L2987(PD-L1 +) vs. HT-29 (PD-L1-) tumors, more than 90% of which could be blocked with 1 nM of BMS-986189. Ex vivo autoradiography showed that ¹⁸ F-BMS-986229 detection was penetrant over a series of sections spanning the entire L2987 tumor. In vivo PET imaging in mice demonstrated a 5:1 tracer uptake ratio (at 90–100 min after tracer administration) in L2987 vs. HT-29 tumors and demonstrated 83%-93% specific binding of BMS-986189 within those dose ranges. In a healthy NHP dosimetry study, the resultant whole-body effective dose was 0.025 mSv/MBq.
Conclusion
¹⁸ F-BMS-986229 has been preclinically characterized and exhibits high target specificity, low background uptake, and a short blood half-life supportive of same day imaging in the clinic. As the PET tracer, ¹⁸ F-BMS-986229 shows promise in the quantification of PD-L1 expression, and its use in monitoring longitudinal changes in patients may provide insights into PD-1:PD-L1 immuno-therapy treatment outcomes.
... It has been demonstrated that radiolabeled PD-1 or PD-L1 antibodies can be used to non-invasively assess PD-1 or PD-L1 expression in NHPs, human tumor xenografts, and syngeneic tumor models [12][13][14][15][16][17]. Although radiolabeled antibodies are used for imaging tumor-speci c proteins, a longer clearance time of radiolabeled antibodies is required for enhanced image contrast and lesion detection. ...
... In this regard, PD-L1 tracers with low molecular weight, faster clearance, short-lived radioactivity, that are relatively easy to radio-synthesize with high speci c activity are desirable for clinical application due to the "same day" imaging feasibility and wider clinical availability. 18 F-BMS986192, an anti-PD-L1 adnectin derived from the 10 th type III domain of human bronectin (~10 kDa) was reported as the rst PD-L1 PET tracer for same-day imaging and has been successfully translated into clinical study application [17][18]. However, its synthesis remains challenging and is isolated in modest yields. ...
... L2987 is a PD-L1 positive human lung adenocarcinoma cell line, while HT-29 is a PD-L1 negative human colorectal adenocarcinoma cell line (American Type Culture Collection) [17]. L2987 cells were cultured in Roswell Park Memorial Institute medium supplemented with 10% fetal bovine serum (FBS), while the HT-29 cells were cultured in Minimum Essentia Media supplemented with 10% FBS. ...
Purpose: In cancer immunotherapy, the blockade of the interaction between programmed death-1 and its ligand (PD-1:PD-L1) has proven to be one of the most promising strategies. However, as mechanisms of resistance to PD-1/PD-L1 inhibition include variability in tumor cell PD-L1 expression in addition to standard tumor biopsy PD-L1 immunohistochemistry (IHC), a comprehensive and quantitative approach for measuring PD-L1 expression is required. Herein, we report the development and characterization of an ¹⁸F-PD-L1-binding macrocyclic peptide as a PET tracer for the comprehensive evaluation of tumor PD-L1 expression in cancer patients.
Procedures: ¹⁸F-BMS-986229 was characterized for PD-L1 expression assessment by autoradiography or PET imaging. ¹⁸F-BMS-986229 was utilized to evaluate tumor PD-L1 target engagement in competition with a macrocyclic peptide inhibitor of PD-L1 (BMS-986189) over a range of doses using PET imaging. A whole-body radiation dosimetry study of ¹⁸F-BMS-986229 in healthy non-human primates (NHPs) was performed.
Results: In vitro autoradiography showed an 8:1 binding ratio in L2987(PD-L1+) vs. HT-29 (PD-L1-) tumors, more than 90% of which could be blocked with 1 nM of BMS-986189. Ex vivo autoradiography showed that ¹⁸F-BMS-986229 detection was penetrant over a series of sections spanning the entire L2987 tumor. In vivo PET imaging in mice demonstrated a 5:1 tracer uptake ratio (at 90-100 minutes after tracer administration) in L2987 vs. HT-29 tumors and demonstrated 83%-93% specific binding of BMS-986189 within those dose ranges. In a healthy NHP dosimetry study, the resultant whole-body effective dose was 0.025 mSv/MBq.
Conclusion: ¹⁸F-BMS-986229 has been preclinically characterized and exhibits high target specificity, low background uptake, and a short blood half-life supportive of same day imaging in the clinic. As the PET tracer, ¹⁸F-BMS-986229 shows promise in the quantification of PD-L1 expression, and its use in monitoring longitudinal changes in patients may provide insights into PD-1:PD-L1 immuno-therapy treatment outcomes.
... This domain has the same high binding affinity and specificity as intact antibodies, and it is small in size (~10 kDa) and easily genetically manipulated [136]. Donnelly et al. developed a tracer using an Adnectin molecule (BMS-986192) with a high binding affinity for PD-L1, 18 F-BMS-986192, which was deemed feasible for the detection of PD-L1 expression in animal tumor models using 18 F-BMS-986192 PET [137]. Later, Nienhuis et al. explored the relationship between lesion uptake of 18 F-BMS986192 and tumor response by using 18 F-BMS-986192 PET to detect PD-L1 expression in patients with metastatic melanoma (Fig. 12 A). ...
Programmed death-1 is a protein found on the surface of immune cells that can interact with its ligand, programmed death-ligand 1 (PD-L1), which is expressed on the plasma membrane, the surface of secreted cellular exosomes, in cell nuclei, or as a circulating soluble protein. This interaction can lead to immune escape in cancer patients. In clinical settings, PD-L1 plays an important role in tumor disease diagnosis, determining therapeutic effectiveness, and predicting patient prognosis. PD-L1 inhibitors are also essential components of tumor immunotherapy. Thus, the detection of PD-L1 levels is crucial, especially in the era of precision cancer therapy. In recent years, innovations have been made in traditional immunoassay methods and the development of new immunoassays for PD-L1 detection. This review aims to summarize recent research progress in tumor PD-L1 detection technology and highlight the clinical applications of PD-L1.
... Some of these drugs are undergoing early clinical studies and have shown good results. Preclinical studies (Table 3) demonstrated the viability of visualizing the biodistribution of PD-L1targeted molecules [61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Radiolabeled PD-L1targeting antibodies accumulated in PD-L1-positive tumors specifically and were also able to differentiate tumors with high and low PD-L1 expressions [61,[63][64][65][66]68]. ...
... Therefore, it is important that we aim to find a developer with a faster removal rate that can provide high-contrast images within hours of injection [76]. Some monoclonal antibody fragments, including single domain antibodies (sdAbs) [71], nanobodies [70,72], and small proteins from adnectin [74] and the PD-1 external domain [77], have been applied in preclinical models. For example, the increased tissue permeability and shorter half-life of single-domain nanobodies enable highcontrast imaging at 1-2 h post-injection. ...
The success of immune checkpoint blockade has reaffirmed the importance of the immune system in cancer treatment. Immunotherapy enables the body's own immune system to fight tumor cells. However, the complex tumor microenvironment and its interaction with the immune system remain a mystery. The efficacy of immunotherapy is often affected by tumor heterogeneity. Molecular imaging techniques, such as single photon emission computed tomography and positron emission tomography, enable noninvasive whole‐body imaging of tumor and immune cell signatures. Noninvasive molecular imaging can also be used to monitor the treatment response of tumors, thereby achieving personalized response assessment, which may ultimately lead to improved clinical management, development of individualized treatments, and reliable prognosis. This article reviews recent research in immunotherapy response assessment, immune T‐cell imaging, immune checkpoint imaging, and radiomics/radiogenomics in immunotherapy. To date, these studies have primarily comprised exploratory preclinical imaging with preliminary results indicating that biomarker molecular imaging may have a role to play in the assessment of immunotherapy. Therefore, the principle of selecting patients for immunotherapy based on imaging results is feasible.
