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Article Open Access

Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment

  • Authors:
    • Huan Du
    • Xiao-Fei Hao
    • Bin-Wei Lin
    • Yu Zhang
    • Luo Rui
    • Jing Wang
    • Ming-Ming Tang
    • De-Cai Wang
    • Yi-Han Zhu
    • Jie Li
    • Tang-Zhi Dai
    • Yuchuan Yang
    • Xia Yang
    • Xiaobo Du
  • View Affiliations / Copyright

    Affiliations: Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan 621000, P.R. China, Department of Nuclear Medicine, Central Hospital of Mianyang, Mianyang, Sichuan 621000, P.R. China, Institute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang, Sichuan 621900, P.R. China, Department of Clinical Medicine, Clinical Medical School, North Sichuan Medical College, Nanchong, Sichuan 637007, P.R. China
    Copyright: © Du et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 4
    |
    Published online on: October 22, 2025
       https://doi.org/10.3892/or.2025.9009
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Abstract

Gastric cancer (GC) is one of the most common types of cancer worldwide, with limited therapeutic options available for patients with advanced‑stage disease. Claudin 18.2 (CLDN18.2) has emerged as a popular target for the diagnosis and treatment of GC. Although antibody‑drug conjugates (ADCs) and radionuclide‑drug conjugates (RDCs) targeting CLDN18.2 have been assessed, to the best of our knowledge, no comparative studies have evaluated the efficacy and toxicity profiles of these two treatment modalities. The present study aimed to compare the antitumor efficacy and toxicity of ADCs and RDCs derived from the same anti‑CLDN18.2 monoclonal antibody (mAb) targeting CLDN18.2‑positive tumors. Modified DFO/DOTA‑SYSA1801mAb, labeled with 89Zr and 177Lu, was used in cell‑based assays, positron emission tomography and biodistribution studies to evaluate its targeting specificity. In an NUGC‑4‑CLDN18.2 xenograft tumor model, the antitumor efficacy and toxicity of the mAb (SYSA1801mAb), as well as the ADC (SYSA1801) and RDC ([177Lu]Lu‑DOTA‑SYSA1801mAb), and their combinations in different sequences (ADC→RDC and RDC→ADC), were systematically assessed. [89Zr]Zr‑DFO‑SYSA1801mAb demonstrated notable in vitro stability and effectively imaged tumors with high CLDN18.2 expression. [177Lu]Lu‑DOTA‑SYSA1801mAb exhibited strong tumor‑targeting ability, with significantly higher tumor uptake than other tissues. By day 145, the complete remission (CR) rate in the ADC group was 60%, with an overall survival (OS) rate of 60%. In the ADC→RDC group, the CR and OS rates were both 40%. The OS rates in the RDC, RDC→ADC, mAb and control groups were all 0%. The ADC group exhibited minimal changes in hematological parameters and hepatic/renal function, whereas the RDC and RDC→ADC groups showed more significant changes. These preclinical findings suggested that ADC monotherapy may demonstrate superior efficacy and safety profiles when compared with RDC monotherapy. Furthermore, sequential combination therapy that starts with ADC appears to be more favorable than approaches that start with RDC. Although ADC→RDC sequential therapy did not significantly outperform ADC monotherapy in this model, it may serve as an effective subsequent treatment strategy.
View Figures

Figure 1

(A) Flow chart of the experimental
design. Created with BioRender.com. (B) Flow cytometry was used to
detect CLDN18.2 expression in NUGC-4-CLDN18.2 cells. Blue line:
Anti-SYSA1801mAb (PE); red line: isotype control (PE). (C)
Radiochemical purity of [177Lu]Lu-DOTA-SYSA1801mAb
determined by HPLC was >99%. Upper panel: Radio-HPLC
(177Lu γ-radiation detection); lower panel:
Ultraviolet-HPLC (254 nm absorption detection). (D) Specific
binding of [177Lu]Lu-DOTA-SYSA1801mAb in NUGC-4-CLDN18.2
cells. Left panel: Saturation binding curve plotted on a
logarithmic concentration scale for calculation of the equilibrium
dissociation constant (Kd). Right panel: Saturation binding curve
plotted on a linear concentration scale for determination of the
maximum binding capacity (Bmax). (E) Stability of
[177Lu]Lu-DOTA-SYSA1801mAb detected by thin-layer
chromatography in normal saline and 1640 (10% FBS). ADC,
antibody-drug conjugate; CLDN18.2, claudin 18.2; EC50,
half maximal effective concentration; FBS, fetal bovine serum;
HPLC, high-performance liquid chromatography; mAb, monoclonal
antibody; RDC, radionuclide-drug conjugate.

Figure 2

(A) Positron emission
tomography-computed tomography images showing tumor-specific
accumulation of [89Zr]Zr-DFO-SYSA1801mAb in
tumor-bearing mice over time, in contrast to that in other
non-target tissues. (B) Quantitative region of interest analysis of
the tumor, heart, liver, spleen, kidney, and muscle in
tumor-bearing mice at 4, 24, 48, 96, 144 and 192 h after injection
of [89Zr]Zr-DFO-SYSA1801mAb. (C) Biodistribution results
at 4, 24, 48, 96 and 144 h after injection of
[177Lu]Lu-DOTA-SYSA1801mAb. (D) Tumor-to-blood, (E)
tumor-to-liver and (F) tumor-to-kidney ratios at 4, 24, 48, 96 and
144 h after injection of [177Lu]Lu-DOTA-SYSA1801mAb.
Data are presented as the mean ± SD. Statistical differences across
the different time points for each ratio were determined by one-way
analysis of variance followed by Tukey's post hoc test for multiple
comparisons. *P<0.05, **P<0.01, ***P<0.001. %DI/g,
percentage of injected dose per gram of tissue; mAb, monoclonal
antibody.

Figure 3

(A) Tumor growth curve of
NUGC-4-claudin 18.2 model in each treatment group. (B) Body weight
change curve for each treatment group. Statistical differences
across the groups were determined by one-way analysis of variance
followed by Tukey's post hoc test for multiple comparisons.
*P<0.05, **P<0.01, ***P<0.001. (C) Kaplan-Meier survival
curves comparing the survival probability of different treatment
groups over time (n=5 mice/group). The log-rank (Mantel-Cox) test
was used to determine statistical significance between groups.
***P<0.001. (D) Pairwise comparisons of survival among key
treatment groups. The P-values result from post-hoc log-rank tests
comparing the indicated groups, with a Bonferroni correction
applied for six pre-specified comparisons (significance threshold:
P<0.0083). *P<0.0083; ns, not significant. ADC, antibody-drug
conjugate; mAb, monoclonal antibody; NS, normal saline; RDC,
radionuclide-drug conjugate.

Figure 4

(A) WBC, RBC and PLT counts of each
treatment group at the end of treatment (n=5 mice/group). (B) BUN,
CREA and UA levels in each treatment group at the end of treatment.
(C) ALB, AST and ALT levels in each treatment group at the end of
treatment. (D) Representative hematoxylin and eosin staining of
tissues collected from euthanized mice from each treatment group.
Statistical differences across the groups were determined by
one-way analysis of variance followed by Tukey's post hoc test for
multiple comparisons. *P<0.05, **P<0.01, ***P<0.001,
****P<0.0001. ADC, antibody-drug conjugate; ALB, albumin; ALT
alanine amino transferase; AST, aspartate aminotransferase; BUN,
blood urea nitrogen; CREA, creatinine; mAb, monoclonal antibody;
NS, normal saline; PLT, platelet; RBC, red blood cell; RDC,
radionuclide-drug conjugate; UA, uric acid; WBC, white blood
cell.
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Copy and paste a formatted citation
Spandidos Publications style
Du H, Hao X, Lin B, Zhang Y, Rui L, Wang J, Tang M, Wang D, Zhu Y, Li J, Li J, et al: Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment. Oncol Rep 55: 4, 2026.
APA
Du, H., Hao, X., Lin, B., Zhang, Y., Rui, L., Wang, J. ... Du, X. (2026). Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment. Oncology Reports, 55, 4. https://doi.org/10.3892/or.2025.9009
MLA
Du, H., Hao, X., Lin, B., Zhang, Y., Rui, L., Wang, J., Tang, M., Wang, D., Zhu, Y., Li, J., Dai, T., Yang, Y., Yang, X., Du, X."Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment". Oncology Reports 55.1 (2026): 4.
Chicago
Du, H., Hao, X., Lin, B., Zhang, Y., Rui, L., Wang, J., Tang, M., Wang, D., Zhu, Y., Li, J., Dai, T., Yang, Y., Yang, X., Du, X."Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment". Oncology Reports 55, no. 1 (2026): 4. https://doi.org/10.3892/or.2025.9009
Copy and paste a formatted citation
x
Spandidos Publications style
Du H, Hao X, Lin B, Zhang Y, Rui L, Wang J, Tang M, Wang D, Zhu Y, Li J, Li J, et al: Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment. Oncol Rep 55: 4, 2026.
APA
Du, H., Hao, X., Lin, B., Zhang, Y., Rui, L., Wang, J. ... Du, X. (2026). Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment. Oncology Reports, 55, 4. https://doi.org/10.3892/or.2025.9009
MLA
Du, H., Hao, X., Lin, B., Zhang, Y., Rui, L., Wang, J., Tang, M., Wang, D., Zhu, Y., Li, J., Dai, T., Yang, Y., Yang, X., Du, X."Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment". Oncology Reports 55.1 (2026): 4.
Chicago
Du, H., Hao, X., Lin, B., Zhang, Y., Rui, L., Wang, J., Tang, M., Wang, D., Zhu, Y., Li, J., Dai, T., Yang, Y., Yang, X., Du, X."Comparative analysis of the efficacy and safety of antibody‑drug conjugates, radionuclide‑drug conjugates and their combination targeting claudin 18.2 in gastric cancer treatment". Oncology Reports 55, no. 1 (2026): 4. https://doi.org/10.3892/or.2025.9009
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