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![Whole-body biodistribution of [⁸⁹Zr]ZrDFO-amivantamab from 6 h to 7 days p.i. (n = 3 per group)](publication/343531313/figure/fig11/AS:941394654941203@1601457384679/Whole-body-biodistribution-of-ZrZrDFO-amivantamab-from-6h-to-7days-pi-n3-per.png)
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![Post-PET biodistribution at 4 days p.i. of [⁸⁹Zr]ZrDFO-amivantamab in...](publication/343531313/figure/fig3/AS:941394650734599@1601457383195/Post-PET-biodistribution-at-4days-pi-of-ZrZrDFO-amivantamab-in-mice-bearing-the_Q320.jpg)
![Stability of [⁸⁹Zr]ZrDFO-amivantamab in PBS at ambient temperature and...](publication/343531313/figure/fig5/AS:941394654949384@1601457384211/Stability-of-ZrZrDFO-amivantamab-in-PBS-at-ambient-temperature-and-in-mouse-and-human_Q320.jpg)
Background
Amivantamab is a novel bispecific antibody that simultaneously targets the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (HGFR/c-MET) that are overexpressed in several types of cancer including triple-negative breast cancer (TNBC). Targeting both receptors simultaneously can overcome resistance to mono...
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Background
CD3 bispecific antibodies (CD3-bsAbs) require binding of both a tumor-associated surface antigen and CD3 for their immunotherapeutic effect. Their efficacy is, therefore, influenced by the absolute tumor uptake and the extracellular dose. To optimize their currently limited efficacy in solid tumors, increased understanding of their pharm...
Citations
... Notably, significant radioactivity was observed at the tumor site, with a favorable target-background contrast at 24 and 36 h. In the study by Cavaliere et al. [77], a radiolabeled bispecific antibody called [ 89 Zr]ZrDFO-Amivantamab was successfully prepared and evaluated for its pharmacological and imaging properties. The researchers compared the imaging quality of Multimodal imaging or multiplexed imaging refers to the simultaneous production of signals for more than one imaging technique. ...
Breast cancer (BC) poses a significant threat to women’s health, with triple-negative breast cancer (TNBC) representing one of the most challenging and aggressive subtypes due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Traditional TNBC treatments often encounter issues such as low drug efficiency, limited tumor enrichment, and substantial side effects. Therefore, it is crucial to explore novel diagnostic and treatment systems for TNBC. Multifunctional molecular probes (MMPs), which integrate target recognition as well as diagnostic and therapeutic functions, introduce advanced molecular tools for TNBC theranostics. Using an MMP system, molecular drugs can be precisely delivered to the tumor site through a targeted ligand. Real-time dynamic monitoring of drug release achieved using imaging technology allows for the evaluation of drug enrichment at the tumor site. This approach enables accurate drug release, thereby improving the therapeutic effect. Therefore, this review summarizes the recent advancements in MMPs for TNBC theranostics, encompassing the design and synthesis of MMPs as well as their applications in the field of TNBC theranostics.
... for in vivo imaging of c-Met. Although these pioneering studies successfully demonstrate the feasibility of imaging C-MET through PET, the antibody-based C-MET probes require relatively long waiting time (at least ~1 day post-injection (p.i.) of the probe) to achieve good imaging contrasts [22,[27][28][29]. 18 F-labeled C-MET binding peptides ( 18 F-AH113804) have also been explored for PET imaging of locoregional recurrence of breast cancer. ...
The mesenchymal epithelial transition factor (c-Met) is frequently overexpressed in numerous cancers and has served as a validated anticancer target. Inter- and intra-tumor heterogeneity of c-Met, however, challenges the use of anti-MET therapies, highlighting an urgent need to develop an alternative tool for visualizing whole-body c-Met expression quantitatively and noninvasively. Here we firstly reported an ¹⁸F labeled, small-molecule quinine compound-based PET probe, 1-(4-(5-amino-7-(trifluoromethyl) quinolin-3-yl) piperazin-1-yl)-2-(fluoro-[18F]) propan-1-one, herein referred as [18F]-AZC.
Methods
[18F]-AZC was synthesized via a one-step substitution reaction and characterized by radiochemistry methods. [18F]-AZC specificity and affinity toward c-Met were assessed by cell uptake assay, with or without cold compound [19F]-AZC or commercial c-Met inhibitor blocking. MicroPET/CT imaging and biodistribution studies were conducted in subcutaneous murine xenografts of glioma. Additionally, [18F]-AZC was then further evaluated in orthotopic glioma xenografts, by microPET/CT imaging accompanied with MRI and autoradiography for co-registration of the tumor. Immunofluorescence staining was also carried out to qualitatively evaluate the c-Met expression in tumor tissue, co-localizes with H&E staining.
Results
This probe shows easy radiosynthesis, high stability in vitro and in vivo, high targeting affinity, and favorable lipophilicity and brain transport coefficient. [18F]-AZC demonstrates excellent tumor imaging properties in vivo and can delineate c-Met positive glioma specifically at 1 h after intravenous injection of the probe. Moreover, favorable correlation was observed between the [18F]-AZC accumulation and the amount of c-Met expression in tumor.
Conclusion
This novel imaging probe could be applied as a valuable tool for management of anti-c-Met therapies in patients in the future.
... Amivantamab is a human bispecific antibody that has been engineered to target both EGFR and c-MET simultaneously, and is currently in phase I trials for metastatic non-small cell lung cancer (NCT02609776) [101]. 89 Zr-labeled amivantamab has been successfully investigated as a PET-imaging CDx in preclinical models of TNBC to assess the combined expression of EGFR and c-MET as well as the delivery of amivantamab to TNBC tumors for therapy [102]. Future clinical studies will help to establish whether this agent could be used to select patients for the treatment of TNBC. ...
One out of eight women will be affected by breast cancer during her lifetime. Imaging plays a key role in breast cancer detection and management, providing physicians with information about tumor location, heterogeneity, and dissemination. In this review, we describe the latest advances in PET/CT imaging of breast cancer, including novel applications of 18F-FDG PET/CT and the development and testing of new agents for primary and metastatic breast tumor imaging and therapy. Ultimately, these radiopharmaceuticals may guide personalized approaches to optimize treatment based on the patient’s specific tumor profile, and may become a new standard of care. In addition, they may enhance the assessment of treatment efficacy and lead to improved outcomes for patients with a breast cancer diagnosis.
... Препарат [ 89 Zr] ZrDFO-амивантамаб предназначен для оценки целесообразности применения таргетного препарата амивантамаб, блокирующего эндотелиальный и гепатоцитарный факторы роста. Два других препарата, созданных на основе биспецифических молекул: 89 Zr-AMG211 и 68 Ga-NGR-RGD -могут использоваться для оценки прогноза заболевания [46][47][48][49]. ...
INTRODUCTION: Triple negative cancer is one of the most aggressive subtypes of breast cancer. Currently, no effective treatment methods have been proposed that would significantly affect the long-term results of treatment.
OBJECTIVE: To summarize the possibilities of theranostics and nanteranostics in the visualization and elimination of malignant cells and immunosuppressive cells of the microenvironment of thriple negative breast cancer.
MATERIALS AND METHODS: A search was conducted for scientific publications in the PubMed information and analytical system for 2015–2022 by keywords: «triple negative breast cancer» («triple negative breast cancer»), «signaling pathways» («signaling pathways»), «tumor microenvironment» («tumor microenvironment»), «cancer stem cells» («stem tumor cells»), «theranostics», «nanomaterials» («nanomaterials»), «nanotheranostics» («nanoteranostics»). After excluding articles devoted to the technical aspects of molecular biological research, 57 publications related to the theranostics of thrice-negative breast cancer were analyzed.
RESULTS: Targets for theranostics of triple negative breast cancer are associated with tumor cells and components of the microenvironment. The article presents data on the composition and interaction between various cellular subpopulations in the tumor microenvironment, as well as on the role of cancer stem cells in its formation. State of art classifications of triple negative breast cancer and data on molecular defects associated with various subtypes are presented. Targets for theranostics associated with stem, differentiated tumor cells and components of the tumor microenvironment are described. The authors present their own data on the nature of the distribution of various subpopulations of the microenvironment, which should be taken into account when choosing the nature of the effect on the tumor. The possibilities and applications of radiopharmaceuticals and nanoparticle-based preparations developed to date have been analyzed.
CONCLUSION: Triple negative breast cancer is characterized by the presence of a large number of biomarkers that can be targets for diagnostic and therapeutic drugs. It is advisable to use artificial intelligence technologies for their selection. The use of nanoparticles makes it possible to reduce toxicity and ensure the implementation of several treatment methods simultaneously.
... One possible way to enhance the binding specificity and targeting efficiency of molecular imaging is to use targeted molecules that can recognize multiple cancer-associated receptors at the same time. Regarding the expression of different markers in tumors, bispecific antibodies have been developed and attracted great attention in cancer diagnosis and therapy [17,18]. Proven biologically safe in clinical trials, EMB01 is a such kind of innovative bispecific antibody engineered to target EGFR and c-Met simultaneously on tumor cells [19]. ...
... Compared with previous studies using single-target antibody probes, bispecific probes offer unparalleled benefits in cancer imaging [18,23]. Tumor heterogeneity regarding the receptor expression may lead to the failure of single-target probes in some negative patients. ...
Purpose
This study aimed to establish a near infrared fluorescent (NIRF) probe based on an EGFR&c-Met bispecific antibody for visualization of esophageal cancer (EC) and metastatic lymph nodes (mLNs).
Methods
EGFR and c-Met expression were assessed by immunohistochemistry. EGFR&c-Met bispecific antibody EMB01 was labeled with IRDye800cw. The binding of EMB01-IR800 was assessed by enzyme linked immunosorbent assay, flow cytometry, and immunofluorescence. Subcutaneous tumors, orthotopic tumors, and patient-derived xenograft (PDX) were established for in vivo fluorescent imaging. PDX models using lymph nodes with or without metastasis were constructed to assess the performance of EMB01-IR800 in differential diagnosis of lymph nodes.
Results
The prevalence of overexpressing EGFR or c-Met was significantly higher than single marker either in EC or corresponding mLNs. The bispecific probe EMB01-IR800 was successfully synthesized, with strong binding affinity. EMB01-IR800 showed strong cellular binding to both Kyse30 (EGFR overexpressing) and OE33 (c-Met overexpressing) cells. In vivo fluorescent imaging showed prominent EMB01-IR800 uptake in either Kyse30 or OE33 subcutaneous tumors. Likewise, EMB01-IR800 exhibited superior tumor enrichment in both thoracic orthotopic esophageal squamous cell carcinoma and abdominal orthotopic esophageal adenocarcinoma models. Moreover, EMB01-IR800 produced significantly higher fluorescence in patient-derived mLNs than in benign lymph nodes.
Conclusion
This study demonstrated the complementary overexpression of EGFR and c-Met in EC. Compared to single-target probes, the EGFR&c-Met bispecific NIRF probe can efficiently depict heterogeneous esophageal tumors and mLNs, which greatly increased the sensitivity of tumor and mLN identification.
... According to Table 2, it is obvious that various octreotide-and octreotate-based beta-emitter labeled RLT agents (e.g., 90 Y/ 177 Lu-DOTATATE and 90 Y/ 177 Lu-DOTATOC) have shown good efficacy in patients with lung NET in several clinical trials [167]. Furthermore, the development of bispecific antibodies or heterodimeric peptides can also improve targeting efficiency and image quality [69,130,156]. Second, radiation toxicity and off-target effects could be further minimized via structure optimization of radionuclide-labeled mAbs. ...
Purpose
This review aims to provide a comprehensive overview of the latest literature on personalized lung cancer management using different ligands and radionuclide-based tumor-targeting agents.
Background
Lung cancer is the leading cause of cancer-related deaths worldwide. Due to the heterogeneity of lung cancer, advances in precision medicine may enhance the disease management landscape. More recently, theranostics using the same molecule labeled with two different radionuclides for imaging and treatment has emerged as a promising strategy for systemic cancer management. In radionuclide-based theranostics, the target, ligand, and radionuclide should all be carefully considered to achieve an accurate diagnosis and optimal therapeutic effects for lung cancer.
Methods
We summarize the latest radiotracers and radioligand therapeutic agents used in diagnosing and treating lung cancer. In addition, we discuss the potential clinical applications and limitations associated with target-dependent radiotracers as well as therapeutic radionuclides. Finally, we provide our views on the perspectives for future development in this field.
Conclusions
Radionuclide-based theranostics show great potential in tailored medical care. We expect that this review can provide an understanding of the latest advances in radionuclide therapy for lung cancer and promote the application of radioligand theranostics in personalized medicine.
... MDA-MB-231 and MDA-MB-468 cells were both derived from the pleural effusion of the patient and are basal subtypes, but there were differences in the genetic backgrounds. Some studies have reported that growth factor receptor (EGFR) levels in MDA-MB-468 were higher than that in MDA-MB-231, which resulted in their different sensitivity to different drugs [35][36][37]. What's more, the difference in PARP-1 and AKT expression between two cell lines was also demonstrated to be associated with sensitivity to cisplatin treatment [38,39]. ...
Objectives
To study the therapeutic effects of lobaplatin in combination with conventional chemotherapy drugs on triple-negative breast cancer (TNBC) cells.
Methods
We used the CCK-8 assay, flow cytometry, western blotting, and immunofluorescence staining methods to detect the effects of lobaplatin or in combination with gemcitabine on the survival, apoptosis, and cell cycle progression of TNBC cells. A cell-derived xenograft mouse model was used to verify the antitumor effects of lobaplatin alone or in combination with gemcitabine.
Results
Lobaplatin significantly inhibited MDA-MB-468 cell growth in vitro, either alone or in combination with gemcitabine. Lobaplatin arrested the cell cycle at the S phase, induced nuclear cell damage, and promoted apoptosis. Also, the percentage of apoptotic cells was greatly increased when lobaplatin was combined with gemcitabine. Cleaved Caspase-3 and Poly (ADP-Ribose) Polymerase-1 (PARP-1) fragments indicated that lobaplatin promoted apoptosis through the classical pathway. Lobaplatin effectively inhibited the growth of tumors in vivo. Compared with the vehicle group (567.6 ± 126.2 mm³), the tumor volume of the lobaplatin group (302.7 ± 131.6 mm³) was significantly reduced (p<0.01). The combination of lobaplatin and gemcitabine (207.7 ± 83.94 mm³) was a little better than lobaplatin alone in the inhibition of the transplanted tumor (p>0.05).
Conclusions
Lobaplatin alone or in combination with gemcitabine had significant inhibitory effects on MDA-MB-468 cells in vitro. Lobaplatin also significantly inhibited the growth of nude mice xenografts. The synergistic effect between lobaplatin and gemcitabine in vivo was minimal, perhaps due to the low dose of gemcitabine used.
... HGF is the natural ligand of c-MET, and thus c-MET is also known as the hepatocyte growth factor receptor (HGFR) [20]. Binding to HGF leads to dimerization and activation of c-MET receptors, which promotes the proliferation, migration, and invasion of tumor cells. ...
Aims:
As one of the most prevalent malignant diseases in the world, the mechanisms of metastasis in colon cancer are poorly understood. The aim of this study was to investigate the role of the HGF/c-MET axis in the proliferation and metastasis in colon cancer.
Methods:
The effect of MACC1 on cell proliferation and metastasis was analyzed through a series of in vitro experiments. The role of MACC1 in cancer cells was demonstrated by overexpression and silencing of MACC1 in gain or loss function experiments. To investigate the relationship between MACC1 and c-MET/HGF, we detected c-MET protein expression by disrupting with or overexpressing MACC1. The bioinformatics analysis was used to investigate the correlation between MACC1 and c-MET, and the c-MET expression after the interference of HGF with MACC1 was determined. Subsequently, the function of c-MET was verified in colon cancer cells by a series of experiments. The mouse tumor transplantation model experiment is most suitable in vivo.
Results:
The results indicated that the overexpression of MACC1 could accelerate proliferation and facilitate metastasis in colon cancer cell lines. Furthermore, c-MET was determined to be the downstream regulator of MACC1. The addition of HGF could stimulate the expression of MACC1. With further exploration, we proved that c-MET is downstream of MACC1 in colon cancer and that overexpression of c-MET in colon cancer enhances cell proliferation and migration capability. At last, MACC1 expression level negatively correlates with the infiltration levels and several immune checkpoint biomarkers. High MACC1 expression has a lower response rate with ICIs in COAD.
Conclusions:
We found that, under the regulation of the MACC1/HGF/c-MET axis, the proliferation and metastasis of colorectal cancer are increased by MACC1, which can be a novel biomarker for predicting ICIs response in colorectal cancer. Our findings provide a new idea for the targeted treatment of colorectal cancer.
... This protocol can be used to determine the K D of each Fab arm separately on immobilized antigens to independently characterize whether the binding affinity of each Fab arm for its respective antigen was affected after radioconjugation. This protocol is demonstrated by the use of radiolabeled amivantamab, a bispecific antibody for epidermal growth factor receptor (EGFR) and cytoplasmic mesenchymalepithelial transition (cMET) proteins 19 . Radiolabeled singlearm antibodies, where one Fab arm binds to EGFR (α-EGFR) or to cMET (α-cMET) and the other Fab arm is an isotype control, were also used as examples 19 . ...
... This protocol is demonstrated by the use of radiolabeled amivantamab, a bispecific antibody for epidermal growth factor receptor (EGFR) and cytoplasmic mesenchymalepithelial transition (cMET) proteins 19 . Radiolabeled singlearm antibodies, where one Fab arm binds to EGFR (α-EGFR) or to cMET (α-cMET) and the other Fab arm is an isotype control, were also used as examples 19 . This protocol is also appropriate for any radiolabeled antibody with a known antigen that can be immobilized. ...
... To ensure the determined K D is accurate, the concentrations of rAb must be high enough to reach saturation. For this assay, radiolabeled antibodies were conjugated to DFO and radiolabeled with 89 Zr, as previously described 19 . Suboptimal experiments for the binding of radiolabeled α-cMET to immobilized cMET proteins are shown in Figure 4 to demonstrate the results of parameters that require optimization. ...
Determining binding affinity (KD) is an important aspect of the characterization of radiolabeled antibodies (rAb). Typically, binding affinity is represented by the equilibrium dissociation constant, KD, and can be calculated as the concentration of antibody at which half the antibody binding sites are occupied at equilibrium. This method can be generalized to any radiolabeled antibody or other protein and peptide scaffolds. In contrast to cell-based methods, the choice of immobilized antigens is particularly useful for validating binding affinities after long-term storage of antibodies, distinguishing binding affinities of fragment antigen-binding region (Fab) arms in bispecific antibody constructs, and determining if there is variability in antigen expression between different cell lines. This method involves immobilizing a fixed amount of antigen to specified wells on a breakable 96-well plate. Then, nonspecific binding was blocked in all wells with bovine serum albumin (BSA). Subsequently, the rAb was added in a concentration gradient to all wells. A range of concentrations was chosen to allow the rAb to reach saturation, i.e., a concentration of antibody at which all antigens are continuously bound by the rAb. In designated wells without immobilized antigen, nonspecific binding of the rAb can be determined. By subtracting nonspecific binding from total binding in the wells with immobilized antigen, specific binding of the rAb to the antigen can be determined. The KD of the rAb was calculated from the resulting saturation binding curve. As an example, binding affinity was determined using radiolabeled amivantamab, a bispecific antibody for epidermal growth factor receptor (EGFR) and cytoplasmic mesenchymal-epithelial transition (cMET) proteins.
... Amivantamab, a bispecific antibody against C-Met and EGFR, has residence time on the surface of breast cancer cells MDA-MB-468, which can increase antibody-dependent cell-mediated cytotoxicity (ADCC). Amivantamab can also cause the degradation of EGFR and c-MET, thus affecting the downstream pathways of cancer cells [53,54]. Cabozantinib is a small molecule inhibitor targeting C-Met and vascular endothelial growth factor receptors (VEGF) that activates the immune system and anti-angiogenesis, and 73% of patients with metastatic triple-negative breast cancer responded to cabozantinib in a phase Ⅱ clinical trial [55,56]. ...
Breast cancer is the most common cancer affecting women's health and its incidence is increasing. With the development of immunohistochemistry and gene expression microarray technology, the study of breast cancer typing has gradually matured, which has also contributed to the development of targeted therapy for breast cancer. At present, the popular breast cancer cell surface markers include: G protein-coupled estrogen receptor 1 [GPER-1], human epidermal growth factor receptor 2 [HER-2], epidermal growth factor receptor [EGFR], c-mesenchymal-epithelial transition factor [C-Met], folate receptor-α [FRα], integrin, programmed death ligand 1 [PD-L1], trophoblast cell surface antigen 2 [Trop-2], etc. Targeted drugs for breast cancer cell surface markers mainly include antibody drugs and small molecule inhibitor drugs, which exert anti-tumor activity by targeting receptors or ligands. This review summarizes the surface markers of breast cancer cells and their targeted drugs, hoping to provide new ideas for breast cancer targeted therapy.
