Research ArticleSupplement

Recent Advances in Radiotracers Targeting Novel Cancer-Specific Biomarkers in China: A Brief Overview

Jingming Zhang, Fei Kang, Xiao Wang, Xuejiao Chen, Xing Yang, Zhi Yang and Jing Wang
Journal of Nuclear Medicine May 2024, 65 (Supplement 1) 38S-45S; DOI: https://doi.org/10.2967/jnumed.123.266314

Abstract

Radiopharmaceuticals play a critical role in nuclear medicine, providing novel tools for specifically delivering radioisotopes for the diagnosis and treatment of cancers. As the starting point for developing radiopharmaceuticals, cancer-specific biomarkers are important and receive worldwide attention. This field in China is currently experiencing a rapid expansion, with multiple radiotracers targeting novel targets being developed and translated into clinical studies. This review provides a brief overview of the exploration of novel imaging targets, preclinical evaluation of their targeting ligands, and translational research in China from 2020 to 2023, for detecting cancer, guiding targeted therapy, and visualizing the immune microenvironment. We believe that China will play an even more important role in the development of nuclear medicine in the world in the future.

In the era of precision medicine, cancers can be identified and reclassified by specific molecular markers, which help to achieve targeted diagnosis and treatment. In China, the incidence rate and mortality of cancer continue to rise along with the aging of the population (1). According to the official “Healthy China 2030” planning outline, the overall early diagnosis rate and 5-y survival rate of common cancers aim to be improved to greater than or equal to 55% and 46.6%, respectively. The concepts of diagnosis and therapy mediated by cancer-specific biomarkers are becoming rapidly accepted. After the revelation of the pathogenesis of cancer and its immune escape mechanism, various novel therapeutic approaches, such as targeted therapies (2–5) and immunotherapies (6), have been developed and have contributed greatly to the advancement of oncology treatments. The success of these therapies is highly dependent on the clear identification of the level of expression of the key biomarkers within the tumor. Therefore, methods for the accurate detection and quantification of these biomarkers become significantly important for solving the clinical demands for patient stratification (7).

Nuclear medicine imaging (PET/CT and SPECT) is an effective method for detecting and staging cancers (8,9). It can provide quantitative information about the level of expression of cancer-specific biomarkers, thus facilitating clinical treatment decision-making. The discovery of novel cancer-specific biomarkers and the development of effective targeted radiopharmaceuticals are essential for enriching the nuclear medicine imaging toolbox. Over the last decades, China has shown rapid development in these areas. Several early reviews have summarized various aspects of this development (10,11). During the last 3 y, researchers in China have actively been continuing to contribute to the development of novel nuclear imaging methods for assisting cancer theranostics. This review presents an updated summary with a focus on radiotracers targeting novel biomarkers.

IMAGING AGENTS FOR CANCER DIAGNOSIS

Cancer specifically overexpresses a range of proteins either in tumor cells or in the microenvironment for promoting the growth and invasion of tumors. These proteins provide characteristic information about tumor tissues and make them ideal nuclear imaging targets for cancer diagnosis. For example, radiopharmaceuticals targeting prostate-specific membrane antigen, a protein highly overexpressed in prostate cancer and tumor neovasculature, can be used for the accurate staging of prostate cancer (12). Fibroblast activation protein, which is specifically overexpressed in cancer-associated fibroblasts, can be used as a pan-cancer target for the diagnosis of a variety of tumors (13). Related studies have been actively pursued in China. In addition to these well-known targets, radiotracers targeting novel biomarkers are also under preclinical and translational studies; these include some targets that have been substantially developed worldwide (e.g., carbonic anhydrase IX (14), integrin αvβ6 (15,16), CD38 (17,18), epithelial cell adhesion molecule (19), glypican 3 (20,21), carcinoembryonic antigen–related cell adhesion molecule 5 (22), and integrin αvβ3 (23)) and some that have been pioneered mainly by Chinese researchers (e.g., galectin (24), integrin α6 (25), and nectin cell adhesion molecule 4 (nectin-4) (26,27)), as shown in Table 1. We selected representative examples for a brief introduction.

View this table:
TABLE 1.

Summary of Novel Radiopharmaceuticals Developed in China from 2020 to 2023

Nectin-4

Nectin-4, also named poliovirus receptor–like 4, is a type I transmembrane cell adhesion molecule of the nectin family (28). It is expressed mainly in the embryo and placenta during fetal development, with expression declining in adulthood. Upregulation of nectin-4 was found in various cancer types, most commonly in urothelial carcinoma, being present in 83% to 97% of tumor samples (28,29). The tumor-specific expression makes nectin-4 an excellent theranostic target. An antibody–drug conjugate targeting nectin-4, enfortumab vedotin (30), was the first such agent approved by the U.S. Food and Drug Administration for treating locally advanced and metastatic urothelial carcinoma (3). Recently, promising results were also observed when enfortumab vedotin was combined with other types of immunotherapies (31).

The diagnostic value of the nectin-4–targeting method has not been fully exploited. In principle, the cancer-specific expression of nectin-4 could provide an imaging method for tumor detection. In 2022, Shao et al. developed a 99mTc-labeled antibody ([99mTc]Tc-HYNIC-mAbNectin-4) for the detection of triple-negative breast cancer (27). This radiotracer showed good detection capability and high specificity for nectin-4–positive tumors, but the prolonged blood circulation half-life of the antibody required over 24 h to reach a good target-to-background contrast.

Low-molecular-weight agents can have good pharmacokinetics and achieve good imaging contrast within 1 h. Recently, Duan et al. constructed a novel nectin-4–targeting radiotracer ([68Ga]Ga-N188) based on the bicyclic peptide scaffold BT8009 (26). [68Ga]Ga-N188 specifically targeted nectin-4–expressing tumors and was rapidly excreted by the kidneys. A translational study was performed on 2 healthy volunteers and 14 patients with advanced bladder cancer using uEXPLORER (United Imaging) total-body PET/CT to determine the pharmacokinetics and tissue distribution of the radiotracer (Fig. 1A). A good correlation between the organ uptake and the nectin-4 expression level was confirmed (Fig. 1B). High sensitivity and specificity could be achieved for bladder cancer detection, showing potential advantages for distinguishing tumors from inflammatory lesions or organs with high [18F]FDG uptake (Figs. 1C and 1D). A recent clinical study involving 62 patients with 16 types of cancer was performed to explore the clinical application of [68Ga]Ga-N188 PET in multiple cancers; the initial results demonstrated a detection rate comparable to that of [18F]FDG PET, improved performance in the detection of residual and recurrent tumors, and lymph node specificity, indicating the potential utility of this method for cancer diagnosis in general.

FIGURE 1.
FIGURE 1.

(A) Dynamic SUVmax of [68Ga]Ga-N188 in selected organs. (B) SUVmax of [68Ga]Ga-N188 at lesions with different nectin-4 expression levels (*** indicates P < 0.001). (C) [68Ga]Ga-N188 and [18F]FDG PET/CT imaging of adrenal metastasis of urothelial cancer (top) and inflamed lymph nodes (bottom). (D) Comparison of [68Ga]Ga-N188 PET/CT, [18F]FDG PET/CT, and MRI of brain metastasis from urothelial cancer. Lesions or inflamed lymph nodes are indicated by arrows. DCE-MRI = dynamic contrast-enhanced MRI; DWI = diffusion-weighted imaging; T2WI = T2-weighted imaging. (Adapted with permission of (26).)

Integrins

Integrins, as a class of cell adhesion transmembrane receptors, are overexpressed in a wide range of cancer types and play a critical role in tumor progression (32). They normally exist as a heterodimer, consisting of an α-subunit and a β-subunit; there are no less than 24 functionally distinct isoforms, categorized into 4 types, including leukocyte cell adhesion integrins, RGD-binding integrins, collagen-binding integrins, and laminin-binding integrins (33). Integrin αvβ3 is a classical target and has attracted worldwide interest for the development of tumor-targeting radiotracers. Recently, a phase 3 clinical trial (NCT04233476) of [99mTc]Tc-3PRGD2 was completed, with results that met both primary and secondary endpoints. It will hopefully be approved soon in China as a novel radiopharmaceutical for cancer diagnosis; its approval could fill the gap in radiopharmaceutical approvals during the last decade. Considering the low cost of SPECT, it may provide an affordable method for people in developing countries or in other areas where the installed PET base may limit access.

Novel radiopharmaceuticals targeting other integrins (e.g., integrins αvβ6 and α6) have also been developed and evaluated in clinical translational studies. Recently, Feng et al. reported a 68Ga-labeled cyclic peptide, [68Ga]Ga-cycratide, based on the integrin αvβ6–targeting RGDLATL sequence (15). Compared with linear peptides, it showed a similar affinity for integrin αvβ6, with improved serum stability and higher tumor uptake. The clinical translational study in patients with pancreatic cancer showed that [68Ga]Ga-cycratide had good pharmacokinetics and could be applied to detecting pancreatic neoplastic lesions and postoperative recurrence (Fig. 2A). Gao et al. reported an integrin α6–targeted radiotracer, [99mTc]Tc-RWY (25), and demonstrated its in vivo specificity in several preclinical animal models as well as its potential for clinical application in 2 patients with breast cancer (Fig. 2B).

FIGURE 2.
FIGURE 2.

(A) [68Ga]Ga-cycratide and [18F]FDG PET/CT images of patients with suspected or postsurgery recurrent pancreatic cancer. Lesions are indicated by red arrows. (B) CT and [99mTc]Tc-RWY SPECT/CT images in different planes (transverse, coronal, and sagittal) of patient with breast cancer. Lesion is indicated by white arrow. Existence of tumor cells and integrin α6 expression were confirmed by hematoxylin–eosin (HE) staining result and integrin α6 immunohistochemistry (IHC) staining result, respectively. (Adapted from (15,25).)

IMAGING AGENTS FOR GUIDING TARGETED THERAPY

Targeted therapy represents one of the most important milestones for cancer treatment. Targeted small molecules or monoclonal antibodies could serve as a “magic bullet” to selectively deliver payloads to the key receptors or functional proteins that promote cancer growth, proliferation, survival, and metastasis to exert anticancer effects. Recently, targeted therapeutic agents experienced accelerated approval for broad clinical applications; these include sacituzumab govitecan for trophoblast cell surface antigen 2 (2), olaparib for poly(adenosine diphosphate–ribose) polymerase (4), and sotorasib for Kirsten rat sarcoma viral oncogene homologue (KRAS) (5). Because of their high specificity, these drugs are effective only in cancer patients carrying the related biomarkers. Assessment of the level of expression of these biomarkers is crucial for patient stratification, and PET imaging may provide an ideal tool for noninvasively quantifying biomarker expression at a molecular level to guide accurate patient selection. Great effort has been made in this direction; radiotracers for antibody–drug conjugate targets (e.g., death receptor 5 (34) and trophoblast cell surface antigen 2 (35)), protein kinase targets (e.g., cyclin-dependent kinase 19 (36), cyclin-dependent kinase 4/6 (37,38), c-Met (39), and platelet-derived growth factor β (40,41)), and others are summarized in Table 1. Among them, the development of radiotracers targeting biomarkers such as cyclin-dependent kinase 19, claudin 18.2 (CLDN18.2), and KRAS is in the early stages and has been pioneered mainly by Chinese scholars. Here we further discuss 2 examples.

CLDN18.2

The CLDN18.2 protein is a tight junctional protein and is 1 of the 2 isoforms of claudin 18 protein (42). It has been found to have limited expression mainly in the tight junctions of differentiated gastric mucosal epithelial cells, functioning in barrier maintenance and paracellular transport (43). Overexpression of CLDN18.2 has been identified in multiple malignancies, such as gastric cancer and pancreatic cancer, making it an excellent therapeutic target (44). Monoclonal antibodies and antibody–drug conjugates against CLDN18.2, such as zolbetuximab, TST001, AB101, SYSA-1801, RC118, and CMG901, have been evaluated in clinical trials to explore their safety and antitumor activity in patients with advanced solid tumors (45).

The boost in CLDN18.2-targeted cancer therapeutics brings up a demand for assessing CLDN18.2 expression for patient stratification. Immuno-PET may provide a straightforward platform for selecting patients and evaluating the treatment response. Zhu’s group evaluated a series of immuno-PET imaging probes, including [124I]I-5C9 (46), [89Zr]Zr-DFO-TST001 (47), and [124I]I-18B10(10 L) (48), for the in vivo detection of CLDN18.2 expression in subcutaneous and orthotopic gastric cancer xenograft models. [124I]I-18B10(10 L) was selected, and a first-in-humans translational study was performed to assess its safety and feasibility for mapping CLDN18.2 expression in 17 patients, including 12 with gastric cancers, 4 with pancreatic cancers, and 1 with cholangiocarcinoma. [124I]I-18B10(10 L) PET could detect most CLDN18.2-overexpressing lesions with an acceptable dosimetry profile and could monitor CLDN18.2 expression status before and after CLDN18.2-targeted treatment (Fig. 3), demonstrating the feasibility of CLDN18.2-targeted imaging.

FIGURE 3.
FIGURE 3.

Representative [124I]I-18B10(10 L) PET images of patient before and after CLDN18.2-targeted therapy. Lesions are indicated by arrows. After receiving CLDN18.2-targeted therapy, SUVmax of peritoneal metastases decreased from 3.1, 3.2, and 4.2 to 0.7, 0.9, and 1.6, respectively, and patient survived for up to 40 wk without progression. (Adapted with permission of (48).)

To improve the pharmacokinetics, single-domain antibodies targeting CLDN18.2 have been actively pursued, with the potential advantages of better tumor penetration and faster tumor uptake than those of conventional monoclonal antibodies. Wei et al. reported a humanized single-domain antibody targeting CLDN18.2 (clone hu19V3) and constructed radiotracers labeled with 68Ga,64Cu, and 18F, which showed moderate tumor uptake with fast renal clearance (49). Zhong et al. developed a humanized single-domain antibody targeting CLDN18.2, fused it with human IgG1 Fc, and labeled it with 89Zr to generate [89Zr]Zr-hu7v3-Fc (50). Compared with the antibody, [89Zr]Zr-hu7v3-Fc was smaller and had a higher affinity, resulting in better tumor penetration and faster tumor uptake. Hu et al. developed a humanized single-domain antibody and fused it with the albumin-binding domain or IgG1 Fc (51). The antibody was radiolabeled with 89Zr and evaluated in preclinical models. Biodistribution results at 12 h after injection showed that the addition of the albumin-binding domain or IgG1 Fc increased tumor uptake by 34.6-fold or 40.7-fold, respectively. With all of the experience accumulated with functionalized single-domain antibodies in preclinical settings, multiple translational studies are currently under investigation.

KRAS

The KRAS gene is one of the most frequently mutated oncogenes among the RAS GTPase family and one of the most common tumor driver mutations (52). The total proportion of the KRAS mutation in tumors is about 30%; it is most common in pancreatic cancer (60%–90%), colorectal cancer (30%–45%), and lung cancer (20%–30%) (53). The G12C mutation of KRAS (KRASG12C) damages the guanosine triphosphate hydrolysis mediated by GTPase-activating protein, increases guanosine triphosphate–bound KRAS, and continuously activates the downstream pathway for the occurrence and maintenance of cancer (54). Therefore, it has been considered an important therapeutic target for a wide range of cancers. KRASG12C-specific inhibitors may provide an effective solution, and 2 inhibitors (sotorasib and adagrasib) have been approved for the treatment of advanced or metastatic KRASG12C non–small cell lung cancer (5,55). The success of the treatment is highly dependent on the existence of the mutation, which is mainly determined by biopsy and tumor gene sequencing. A noninvasive molecular imaging method could provide an ideal solution to overcome the limitations caused by tumor heterogeneity.

In 2021, Zhang et al. reported a radiolabeled small molecule, [131I]I-ARS-1620, for imaging of the KRASG12C status of tumors in vivo (56). The in vivo imaging results showed that A549 tumors with KRASG12C could be specifically detected at 1 h after injection, with a tumor-to-muscle ratio of 2.2 ± 0.48 (mean ± SD), and no significant uptake was detected in either the KRASG12C-negative A549 tumor group or the ARS-1620 blocking group.

Recently, Li et al. reported another novel radiotracer derived from AMG510 (sotorasib), [18F]PFPMD, for the PET imaging of KRASG12C status in vivo (57). It can bind to KRASG12C with higher selectivity than KRASWT (wild type), KRASG12D, or KRASG12V. The PET imaging results showed significantly higher uptake in KRASG12C mutated tumors than in non–KRASG12C mutated tumors in a preclinical mouse model (3.93 ± 0.24 %ID/g vs. 2.47 ± 0.26 %ID/g). A translational study was performed with 5 healthy volunteers and 14 patients with non–small cell lung cancer or colorectal cancer to assess safety, dosimetry, and KRASG12C imaging capability. The results showed that [18F]PFPMD was safe and primarily excreted through the kidney and intestines (Fig. 4A). The SUVmax of tumors with KRASG12C was higher than that of those without the mutation (Fig. 4B) in both patients with non–small cell lung cancer (3.56 ± 0.67 vs. 2.45 ± 0.21) and patients with colorectal cancer (3.90 ± 0.53 vs. 2.48 ± 0.29), indicating the potential of this radiotracer for the clinical evaluation of KRASG12C.

FIGURE 4.
FIGURE 4.

(A) Representative [18F]PFPMD PET images of healthy volunteer at different time points after injection. (B) Representative [18F]PFPMD PET/CT images of non–KRASG12C-expressing and KRASG12C-expressing tumors in patients with non–small cell lung cancer and colorectal cancer. KRAS mutation status of tumors was determined by amplification-refractory mutation system polymerase chain reaction or targeted 425-gene sequencing, with KRASG12C mutant lesions indicated by red arrows and non-KRASG12C mutant lesions indicated by white arrows. (Adapted from (57).)

IMAGING AGENTS FOR VISUALIZING IMMUNE MICROENVIRONMENT

Immunotherapy has brought revolutionary changes to cancer management. Unlike other types of cancer therapy, immunotherapy aims to activate the host immune system to exert anticancer effects (58). This unique feature allows it to achieve a clinical response to a wide range of cancer types (6). Immune infiltration in the tumor microenvironment and the maintenance of its effector functions are crucial for the efficacy of immunotherapy. However, the high complexity and heterogeneity of the tumor microenvironment result in variable therapeutic responses, and only a subset of patients benefit from immunotherapy. Therefore, it is important to develop reliable methods for patient stratification and monitoring of the efficacy of immunotherapy. A variety of novel radiotracers targeting immune-related biomarkers, such as programmed cell death protein 1 (59), programmed cell death ligand 1 (60), CD8 (61), T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) (62,63), CD47 (64), and stimulator of interferon genes (STING) (65,66), have been developed for visualizing the immune microenvironment and predicting or monitoring the treatment response. Some of them, such as radiotracers targeting CD8, granzyme B, TIGIT, CD47, and very late antigen 4, were developed on the basis of relevant studies conducted outside China. In addition, some, such as radiotracers targeting intercellular adhesion molecule 1 (ICAM-1) and STING, were originally developed by Chinese researchers. The progress made in this field in China during recent years is summarized in Table 1, and 2 representative examples are discussed here.

Granzyme B

Granzyme B is a serine esterase mainly excreted by cytotoxic T lymphocytes and natural killer cells. Within target cells, granzyme B rapidly activates the caspase cascade reaction and triggers cell apoptosis by inducing DNA fragmentation (67). Granzyme B secretion is a key step in a variety of antitumor immunotherapies, reflecting not only cytotoxic T-cell infiltration at the tumor site but also the functional status of immune cells (68). Therefore, radiotracers targeting granzyme B secretion can provide a direct indication of the tumor-killing effect of immune cells and potentially help to predict the response to immunotherapy (69).

In 2022, Zhou et al. developed a 68Ga-labeled peptidomimetic agent, [68Ga]Ga-grazytracer, for granzyme B–targeted PET imaging (70). Compared with the peptide-based PET imaging ligand [68Ga]Ga-NOTA-GZP (69), [68Ga]Ga-grazytracer showed improved potency and metabolic stability, which resulted in higher tumor uptake and tumor-to-muscle ratio. The efficiency of [68Ga]Ga-grazytracer in monitoring early tumor responses to immune checkpoint inhibitors and adoptive T-cell transfer therapy was investigated in preclinical mouse models. A positive relationship between tumor uptake and therapeutic outcome was observed. [68Ga]Ga-grazytracer PET could differentiate tumor pseudoprogression on immune checkpoint inhibitor treatment from true progression, demonstrating a potential advantage over [18F]FDG PET. In addition, a clinical translational study of [68Ga]Ga-grazytracer was performed. Patients undergoing immune checkpoint inhibitor treatment were imaged after treatment initiation. The results showed that the treatment responders had higher granzyme B PET tumor SUVmax and tumor–to–blood pool ratio than nonresponders (Figs. 5A and 5B); these results were consistent with the immunochemistry staining results. With the potential of [68Ga]Ga-grazytracer having been demonstrated, a systematic clinical investigation would have merit and is currently under way.

FIGURE 5.
FIGURE 5.

[18F]FDG and [68Ga]Ga-grazytracer PET images of lung cancer patients treated with immunotherapy. [18F]FDG SUVmax of both patients decreased after immunotherapy; however, patient with higher [68Ga]Ga-grazytracer uptake (SUVmax, 4.1; tumor–to–blood pool SUVmax ratio, 1.2) showed positive response (A), and patient with lower [68Ga]Ga-grazytracer uptake (SUVmax, 2.0; tumor–to–blood pool SUVmax ratio, 0.8) showed negative response (B). Red arrows indicate primary tumors. (Adapted from (70).)

ICAM-1

ICAM-1, also known as CD54, is a member of the immunoglobulin superfamily of adhesion molecules expressed mainly on endothelial cells and leukocytes (71). It plays a key role in innate and adaptive immune responses and promotes the activation and migration of lymphocytes by interacting with leukocyte integrins such as lymphocyte function–associated antigen 1 and Mac1 (72,73). Recently, Zhao et al. discovered that ICAM-1 played an important role in the abscopal effect of tumor radiation therapy and that ICAM-1–targeted imaging can be used for prediction of the responses to radiation therapy in combination with immunotherapy (74). Tumors were inoculated on both left and right flanks of BALB/c mice, and only 1 was irradiated to mimic the clinical scenario of a primary tumor and its metastatic lesions (Fig. 6A). Significant upregulation of ICAM-1 in nonirradiated tumors with a smaller change in tumor volume was identified by quantitative proteomic analysis. Further mechanistic studies showed that ICAM-1 improved the abscopal effect by increasing the infiltration and activation of CD8+ T cells within the tumor. A 64Cu-labeled ICAM-1–specific PET imaging radiotracer, [64Cu]Cu-NOTA-αICAM-1/Fab, was constructed and succeeded in noninvasive monitoring of ICAM-1 expression levels and early prediction of the abscopal effect of tumor radiotherapy in 4T1 and CT26 tumor–bearing mouse models, with good contrast and specificity (Figs. 6B and 6C). The feasibility of using ICAM-1 PET to predict the abscopal effect during radiotherapy has been demonstrated, and a radioligand with improved pharmacokinetics and suitable for 18F and 68Ga labeling would facilitate translational research.

FIGURE 6.
FIGURE 6.

(A) Schedule of x-ray radiotherapy (X-RT) and in vivo imaging in 4T1 tumor–bearing mice. (B) Representative small-animal PET images of [64Cu]Cu-NOTA-αICAM-1/Fab in 4T1 tumor–bearing mice at 6 h after injection, with red circles indicating location of nonirradiated tumors. (C) Growth curves of nonirradiated 4T1 tumors (** indicates P < 0.01). %ID/g = percentage injected dose per gram; NIRF = near-infrared fluorescence; V = tumor volume at day n; V0 = tumor volume at day 0. (Adapted with permission of (74).)

CONCLUSION

The last 3 y have witnessed the rapid development of radiopharmaceuticals in China. A variety of novel tumor-related biomarkers, such as nectin-4, KRAS, CLDN18.2, and granzyme B, have been exploited as targets for tumor diagnosis or prediction of the treatment response, and progress has been made in the development of high-quality ligands targeting these biomarkers. For multiple radiotracers, first-in-humans clinical translation has been achieved. Besides monoclonal antibodies and small molecules, a variety of functionalized peptides and antibody fragments (e.g., Fab and single-domain antibody) with suitable pharmacokinetics matching those of short–half-life nuclides (18F and 68Ga) have also been actively pursued. In addition to diagnostic usage, radionuclide therapy is another attractive application area for nuclear medicine. Biomarkers with membrane localization, limited expression in normal tissues, and upregulation in cancer are ideal targets for radionuclide therapy application. Some of them, such as integrin αvβ3, trophoblast cell surface antigen 2, CD47, and CLDN18.2, have been tested in preclinical models for radionuclide therapy. In addition, other biomarkers with good tumor specificity and imaging potential, such as nectin-4, glypican 3, integrin α6, epithelial cell adhesion molecule, and death receptor 5, can also be exploited for radionuclide therapy.

However, there are still limitations that may require further efforts. First, the number of radiopharmaceuticals targeting innovative targets remains low and needs to be further explored. Second, the performance of innovative radiopharmaceuticals still needs systematic evaluation in well-designed prospective cohort studies. With improved accessibility of screening methods (e.g., cyclic peptide and single-domain antibody) and accumulated experience (e.g., radiolabeling and patient management), greatly accelerated development of and translational research on radiopharmaceuticals are expected in China in the near future.

DISCLOSURE

This study was supported by National Natural Science Foundation of China grants (92059101 and 22277002 to Xing Yang; 91959208, 92259304, and 82122033 to Fei Kang). No other potential conflict of interest relevant to this article was reported.

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  • Received for publication October 31, 2023.
  • Revision received January 23, 2024.
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