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Figure 1.
The protein structure and function of CLDN18.2. CLDN18.2 contains four transmembrane domains, two extracellular loops (ECL1 and ECL2), one intracellular loop, and cytoplasmic N- and C-terminal regions. ECL1 contains major epitopes recognized by therapeutic antibodies, while ECL2 contributes to claudin-claudin interactions and intercellular adhesion.
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Figure 2.
Regulatory mechanisms of CLDN18.2 expression in PDAC. CLDN18.2 in pancreatic ductal adenocarcinoma (PDAC) is regulated by promoter methylation, ZIC2/ERK1/2 signaling, microRNAs, O-GlcNAcylation, and immune-mediated remodeling. O-GlcNAcylation at T204 reduces membrane CLDN18.2, weakens protein tyrosine phosphatase 1B (PTP1B) binding, increases phosphorylation, and promotes Src recruitment, thereby enhancing invasion, metastasis, and treatment resistance. KRAS G12D inhibition may reverse this process by reducing O-GlcNAcylation and restoring membrane localization. CLDN18.2 can also be transferred from tumor cells to CD8+ T cells through ALCAM-CD6-mediated trogocytosis, driving β-catenin-dependent metabolic reprogramming, T-cell dysfunction, systemic immunosenescence, and tumor progression. PC18.1 may restore T-cell function by blocking CLDN18.2-β-catenin interaction.
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Figure 3.
The mechanisms of CLDN18.2-targeted therapies. Multiple therapeutic modalities are shown: (1) monoclonal antibodies (mAbs), which mediate tumor cell killing mainly through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC); (2) antibody-drug conjugates (ADCs), which bind CLDN18.2 and deliver cytotoxic payloads to CLDN18.2-expressing tumor cells; (3) bispecific antibodies (BsAbs), including CLDN18.2/CD3 T-cell engagers that redirect T cells toward CLDN18.2-positive tumor cells and CLDN18.2/CD47 BsAbs that block the CD47-SIRPα 'don't eat me' axis to enhance macrophage-mediated phagocytosis; and (4) chimeric antigen receptor T-cell (CAR-T cell) therapy, which uses engineered T cells to recognize CLDN18.2-positive tumor cells and induce cytotoxic killing.
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Figure 4.
CLDN18.2-targeted therapies for PDAC.
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Mechanism Drug Trial ID Phase Enrollment Condition Status Treatment regimen Line of setting Primary endpoint mAb Zolbetuximab NCT06396091 1 12 PC Active_not_recruiting Zolbetuximab+mFFX 1L metastatic AE, DLT, ECOG PS Zolbetuximab NCT03816163 2 393 PC Active_not_recruiting Zolbetuximab+AG 1L metastatic AE, DLT, OS, ECOG PS FG-M108 NCT07383922 3 524 PC Not_yet_recruiting FG-M108+AG 1L LA/metastatic OS TST001 NCT04396821 1/2 150 PC, GC, GEJ Active_not_recruiting TST001+AG 1L LA/metastatic AE, MTD, DLT FG-M108 NCT04894825 1 152 Solid tumors Unknown FG-M108 monotherapy LA/metastatic AE, MTD TORL-2-307-MAB NCT05159440 1 70 Solid tumors Active_not_recruiting TORL-2-307-MAB monotherapy LA/metastatic AE, MTD, RP2D AB011 NCT04400383 1 62 Solid tumors Completed AB011 monotherapy, AB011+AG ≥ 2L metastatic AE, DLT BsAb ANO31905 NCT07444541 1/2 84 PC Not_yet_recruiting ANO31905+AG 1L LA/metastatic DLT, ORR ASP2138 NCT07024615 1 25 PC Recruiting Neoadjuvant ASP2138 monotherapy Neoadjuvant AE, ECOG PS QLS31905 NCT07079228 3 602 PC Recruiting QLS31905+AG 1L LA/metastatic OS ASP2138 NCT05365581 1 398 PC, GC, GEJ Recruiting ASP2138 monotherapy, ASP2138+mFFX LA/metastatic AE, DLT, ECOG PS AZD5863 NCT06005493 1/2 280 PC, GC, GEJ, EC Recruiting AZD5863 monotherapy ≥ 2L metastatic AE, DLT, ORR PT886 NCT05482893 1/2 258 PC, GC, GEJ, BTC Recruiting PT886+AG, PT886+FOLFIRINOX/mFFX ≥ 2L metastatic MTD, DLT IBI389 NCT05164458 1 320 Solid tumors Unknown IBI389 monotherapy, IBI389+ IBI308 LA/metastatic AE, DLT CAR-T CLDN18.2 CAR-T NCT07416240 Early_1 10 PC Recruiting Claudin 18.2 CAR-T monotherapy ≥ 3L metastatic AE LY011 NCT04966143 Early_1 30 PC Unknown LY011 monotherapy ≥ 2L metastatic ORR CT041 NCT05911217 1 20 PC Recruiting CT041 injection after adjuvant chemotherapy Adjuvant DFS Mesothelin and CLDN 18.2 CAR-T NCT07066995 1/2 60 PC Recruiting Mesothelin and Claudin 18.2 CAR-T monotherapy ≥ 2L metastatic DLT, MTD CBG131 NCT07394205 Early_1 18 PC, GC Not_yet_recruiting CBG131 monotherapy ≥ 2L metastatic AE, DLT, MTD, RP2D CBG131 NCT05620732 1 20 PC, GC Recruiting CBG131 monotherapy ≥ 3L metastatic AE HEC-016 NCT05277987 Early_1 18 PC, GC, GEJ Unknown HEC-016 monotherapy ≥ 2L metastatic DLT CT048 NCT05393986 1 63 PC, GC, GEJ Unknown CT048 monotherapy ≥ 2L metastatic DLT, MTD IMC002 NCT05472857 1 30 PC, GC, GEJ, AOC Recruiting IMC002 monotherapy 1L LA/metastatic AE, MTD, DLT LB1908 NCT05539430 1 56 PC, GC, GEJ, EC Active_not_recruiting LB1908 monotherapy ≥ 2L metastatic RDE, RP2D KD-496 NCT05583201 1 18 Solid tumors Recruiting KD-496 monotherapy ≥ 2L metastatic TEAE, DLT, CAR-T cells KD-496 NCT06134960 1 12 Solid tumors Not_yet_recruiting KD-496 monotherapy ≥ 3L metastatic AE, DLT CT041 NCT04404595 1/2 110 PC, GC Active_not_recruiting CT041 monotherapy ≥ 2L metastatic AE, DLT, MTD/MAD, ORR CT041 NCT04581473 1/2 192 PC, GC, GEJ Active_not_recruiting CT041 monotherapy ≥ 2L metastatic AE, MTD, PFS ADC LM-302 NCT07108504 2 30 PC Not_yet_recruiting LM-302+GEM 2L metastatic ORR IBI343 NCT06770439 2 64 PC Recruiting IBI343+AG LA/metastatic AE, ORR IBI343 NCT07415525 2 40 PC Not_yet_recruiting IBI343+AG Neoadjuvant EFS IBI343 NCT07066098 3 201 PC Recruiting IBI343 monotherapy ≥ 3L metastatic OS DA-3501 NCT07481357 1 51 PC, GC, GEJ Not_yet_recruiting DA-3501 monotherapy LA/metastatic MTD, ORR IBI343 NCT05458219 1 470 Solid tumors Recruiting IBI343 monotherapy, IBI343+FOLFIRINOX/mFFX LA/metastatic AE, DLT, ORR TORL-2-307-ADC NCT05156866 1 163 Solid tumors Active_not_recruiting TORL-2-307-ADC monotherapy LA/metastatic AE, MTD, RP2D AZD0901 NCT04805307 1 176 Solid tumors Completed AZD0901 monotherapy ≥ 2L metastatic AE, MTD, ORR LM-302 NCT05001516 1 17 Solid tumors Completed LM-302 monotherapy ≥ 2L metastatic AE, DLT XNW27011 NCT06792435 1/2 240 PC, NSCLC, OC, CRC, BTC, GC, GEJ Recruiting XNW27011 monotherapy ≥ 2L metastatic ORR, MTD, RP2D AZD4360 NCT06921928 1/2 117 PC, GC, GEJ, BTC Recruiting AZD4360 monotherapy ≥ 2L metastatic AE, MTD AZD0901 NCT06219941 2 224 PC, GC, GEJ, BTC Recruiting AZD0901 monotherapy, AZD0901+AG/FOLFIRINOX LA/metastatic AE, ORR IBI343 NCT07483554 2 389 PC, GC, GEJ Not_yet_recruiting IBI343+AG LA/metastatic AE, ORR * This information is available on https://clinicaltrials.gov/ , accessed on 21 March 2026.Table 1.
Ongoing trials of anti CLDN18.2 in PDAC*.
Figures
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Tables
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