CLDN18.2 underexpression

Our findings illuminated the role of the CLDN18.2-mediated interaction between cancer cells and CAFs in promoting gastric cancer progression and embolism, thereby providing insight into potential therapeutic avenues for CLDN18.2 positive cancers. Video Abstract.

Three types of DSAs with high levels of CLDN18 expression, GAD, GBAD, and PAAD, may benefit most from future anti-CLDN18 therapies. The correlations of the expression of CLDN18 with clinicopathological characteristics and prognosis suggest that the patients at an early stage could benefit more from the future anti-CLDN18 treatment and CLDN18 can function as a pivotal regulative molecule in GBAD.

ZL-1211, anti-CLDN18.2 therapeutic antibody can target CLDN18.2-high as well as -low gastric cancers that may not be eligible for treatment with clinical benchmark. ZL-1211 treatment induces NK-cell activation with robust inflammation to further activate antitumor immunity in tumor microenvironment.

In a CLDN18.2-high patient-derived xenograft (PDX) PC tumor model, increasing doses of TPX-4589 demonstrated superior tumor growth inhibition compared to gemcitabine and LM-102, a compound with identical anti-CLDN18.2 mAb component as LM-302, and similar efficacy to LM-102 + gemcitabine in combination. TPX-4589, a novel CLDN18.2-targeting ADC, showed potent inhibitory effects on tumor cell proliferation in vitro and reduced tumor volume in both high- and low-expressing CDLN18.2 tumor models, with superior internalization and efficacy to zolbetuximab in a GC tumor model. These data suggest that TPX-4589 is a promising therapeutic candidate that warrants further investigation in clinical studies.

The negative correlation between AFP and CLDN18.2 could be explained by retro-differentiation of AFPGC. Special treatment strategies might be needed for this unique tumor type.

Survival analysis showed that a longer median progression-free survival (mPFS) was not related to peptide reactivity (p = 0.997), but related to a lower Claudin18.2 expression level (p = 0.047). These findings establish a foundation for the clinical application of Claudin18.2 targeted T cell-based immunotherapy in GC.

The monoclonal antibody targeting CLDN18.2 (IMAB362) has demonstrated promising clinical benefit in combination with chemotherapies for gastric cancer patients. ATG-022 demonstrated potent in vitro and in vivo antitumor effects, with in vivo efficacy observed in CLDN18.2-low expression PDX models, suggesting a promising therapeutic strategy for gastric cancer patients with a broad range of CLDN18.2 expression levels.

Taken together, our data suggest that ZL-1211 more effectively targets CLDN18.2-high gastric cancers as well as -low expressing malignancies that are not eligible for treatment with the leading clinical benchmark by inducing a robust ADCC response and activating innate and adaptive immunity to enhance anti-tumor efficacy. Clinical activity of ZL-1211 is currently under evaluation in a Phase I clinical trial (NCT05065710).