CLDN18.2 overexpression

Inhibiting autophagy by autophagy inhibitor LY294002 remarkably enhanced αCLDN18.2-MMAE-induced cytotoxicity and caspase-mediated apoptosis, indicating the cytoprotective role of autophagy in CLDN18.2-directed ADC-treated gastric cancer cells...Besides, the Akt/mTOR pathway inactivation was demonstrated to be implicated in the autophagy initiation in αCLDN18.2-MMAE-treated gastric cancer cells. In conclusion, our study highlighted a groundbreaking investigation into the mechanism of the CLDN18.2-directed ADC, focusing on the crucial role of autophagy, providing a novel insight to treat gastric cancer by the combination of CLDN18.2-directed ADC and autophagy inhibitor.

The activity of perioperative chemotherapy-free immune checkpoint regimens in patients with nonmetastatic dMMR/MSI-H cancer is highly promising and underscores the need to identify this unique subgroup. We recommend MMR/MSI testing for all patients with GEA at diagnosis, and review the key rationale and clinical management implications for patient with dMMR/MSI-H tumors across disease stages.

Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed HER2, and has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting VEGFR2 and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed FGFR2, while zolbetuximab targets overexpressed CLDN18.2, significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer; and the treatment strategies for gastric cancer based on targeting HER2, VEGF, FGFR2, CLDN18.2, MET and other tumor driver genes, aiming to provide reference for clinical application of targeted therapy for gastric cancer.

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.

The Ga-DOTA-T37 probe exhibits good in vitro properties and high stability as a hydrophilic probe; it has high biological safety, and positron emission tomography/computed tomography (PET/CT) studies have shown that it can specifically target CLDN18.2 protein and CLDN18.2-positive tumors in mice. Ga-DOTA-T37 demonstrated the superiority and feasibility of using a CLDN18.2-specific probe in PCT/CT imaging, which deserves further development and exploitation.

In preclinical studies, [Lu]Lu-TST001 demonstrated significant antitumor efficacy with acceptable toxicity. It exhibits strong potential for clinical translation, providing a new promising treatment option for CLDN18.2-overexpressing tumors, including GC.

In conclusion, claudin 18.2 was overexpressed in almost half of resectable gastric cancer patients. Claudin 18.2 overexpression was associated with some clinicopathological characteristics, but was not an independent prognostic factor in a localized setting.

More recently, two monoclonal antibodies have demonstrated their efficacy in combination with oxaliplatin-based first-line chemotherapy, nivolumab (anti-PD1) for PD-L1 CPS ≥5 tumors, and zolbetuximab for tumors overexpressing Claudin 18.2. Recent years have seen the emergence of new drugs that have improved patient survival, such as trastuzumab in first-line for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel in second-line, and trifluridine-tipiracil beyond the second-line treatment. Advanced gastric adenocarcinoma is a common disease with a poor prognosis whose treatment has for decades been based on cytotoxic chemotherapy, including platinum salts in first-line, and taxane or irinotecan in second or later line. In addition, regorafenib has been also showed effective in phase 3 trial for heavily pretreated patients. Based on phase 2 studies, trastuzumab-deruxtecan was approved in 2022 by the EMA for HER2-positive pretreated patients. This agent is currently evaluated in phase 3 study (DESTINY-Gastric04 trial), as are several other anti-HER2 (zanidatamab, margetuximab, tucatinib), immune checkpoint inhibitors, or targeted therapies (anti-FGFR2b).

CLDN18 is frequently expressed in PDAC, and high CLDN18-expressing PDACs showed some different clinicopathologic characteristics. High CLDN18 expression was not associated with prognosis in patients with surgically resected PDAC.

Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunogenically "cold" tumors.

Conclusions Biomarker co-expression may be frequent in the CDLN18.2+ve subset, and CLDN18.2+ve/HER2+ve may reveal a genomically more complex subgroup. Evaluation in larger datasets is required to understand its biological significance and potential therapeutic implications.

Encouraging anti-tumor activities have been observed regardless of the CLDN18.2 expression levels, including expression as low as ≥10% tumor cells staining ≥1+, <40% tumor cells staining <2+ or 3+. Overall survival data will be presented.

I-18B10(10L) was successfully prepared and exhibited a high binding affinity and CLDN18.2 specificity in preclinical studies. As an FiH CLDN18.2 PET tracer, I-18B10(10L) was shown to be safe with acceptable dosimetry and to clearly reveal most lesions overexpressing CLDN18.2.

A dosimetry estimation study showed that the effective dose of &lsqb;Zr]Zr-DFO-TST001 was 0.0705 mSv/MBq, which is within the range of acceptable doses for nuclear medicine research. Taken together, these results suggest that Good Manufacturing Practices produced by this immuno-positron emission tomography probe can detect CLDN18.2-overexpressing tumors.

Funding: Suzhou Transcenta Therapeutics Co., Ltd.Background: Claudin18.2 antibody plus chemotherapy is a clinically validated approach for patients with high CLDN18.2 expressing tumors, which has been proven by zolbetuximab. Osemitamab plus CAPOX as first-line treatment for patients with G/GEJ cancer demonstrated good safety and tolerability. Encouraging anti-tumor activities have been observed regardless of the CLDN18.2 expression levels above 10%, 1+ per central LDT assay.

Zolbetuximab, an anti-CLDN18.2 monoclonal antibody, plus chemotherapy has outperformed chemotherapy alone in a global biomarker-informed phase 3 study in the front-line setting, and interest is growing in exploring CLDN18.2-targeted agents in the perioperative space... CLDN18.2+ve and CLDN18.2-ve tumours had similar genomic and immune signatures. However, nCT substantially contributes to CLDN18.2 spatial and temporal heterogeneity. Larger cohorts will need to confirm these findings, which could have implications for therapy.

JPYZ has an inhibitory effect on GC growth and metastasis partly by elevating CLDN18.2 abundance in GC cells, indicating more patients may benefit from combination therapy of JPYZ and the upcoming CLDN18.2 target agents.

HER-2 expression is low and CLDN18.2 expression is high in patients with PDAC. HER-2 expression is not related to overall survival but CLDN18.2 is related and may be used as a prognostic marker in patients with PDAC.

In average group, no regimen showed significant improvements in overall survival (OS) and progression free survival (PFS), while pembrolizumab and nivolumab combined with chemotherapy were ranked first and second respectively without an obvious safety difference...The top three regimens were zolbetuximab-chemotherapy, trastuzumab plus pertuzuma-chemotherapy and nivolumab-chemotherapy respectively, with no significant safety risk. For average patients, immune checkpoint inhibitor PD-1 plus chemotherapy will be the promising regimen. For patients with overexpression of CLDN18.2, zolbetuximab combined with chemotherapy comes with greater survival benefits, while for patients who have PD-L1 expression with no HER-2 or CLDN18.2 positivity, additional immune checkpoint inhibitor of PD-1 will be a good considered option.

Under the expanded protocol amendment, 95 of ~140 sites in North America, Latin America, Europe, and Asia Pacific were activated. Clinical trial information: NCT03816163.

With CLDN18.2 high, CPS≥1 was associated with longer survival in AGC treated with NIVO.

Chemotherapy, such as gemcitabine, increased CLDN18.2 mRNA and protein expression levels in cancer cells and sensitized tumor cells to ZL-1211-mediated ADCC. Furthermore, ZL-1211 in combination with SoC chemotherapies, oxaliplatin + capecitabine (CAPOX), enhanced anti-tumor efficacy in SNU601 gastric cancer xenograft model...Conclusions These data provide rationale to combine ZL-1211 with SoC chemotherapy in gastric cancer. Currently, a phase I dose escalation study is underway to assess the safety, tolerability, pharmacodynamics, and pharmacokinetics of ZL-1211 in patients with advanced solid tumors ( NCT05065710 ).

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.

Both anti-CLDN18.2 VHH-ABD and anti-CLDN18.2 VHH-Fc can be efficiently and stably radiolabeled with Zr for noninvasive imaging and quantification of CLDN18.2 expression in gastric cancer, of which Zr-anti-CLDN18.2 VHH-ABD seems to be the optimal choice balancing tumor uptake and liver background. They can provide essential information to select patients who are likely to benefit from CLDN18.2-targeted treatment.

Data will be presented using descriptive statistics for continuous endpoints and frequency and percentage for categorical endpoints. At original protocol enrollment completion (October 2021), 84 sites were actively recruiting; sites are currently reopening for screening/enrollment pending protocol amendment approval.

TST001 in combination with CAPOX in first line gastric cancer patients is safe and encouraging anti-tumor activities have been observed. Additional data from the 6 mg/kg dose expansion cohort will be updated at the meeting.

In terms of in vivo ADCs assessment, our abundant CDX and PDX resource facilitates the process of in vivo ADCs evaluation, and we have already assess the efficacy of ADC or the combination treatment of ADC and other anti-tumor drugs in several animal models. Last but not the least, our high-throughput MSD (MESO QuickPlex) and Luminex (Bio-PlexTM 200 system) platform boosts the evaluation of ADCs safety by measuring the extent of cytokine release syndrome.

These data support the proof of concept of the PACbody™ and SPECpair™ technology platforms and demonstrate the unique profile of our anti-CD47 arm that’s suitable for the bispecific antibody approach. PT886 is a first-in-class anti-CLDN18.2/anti-CD47 bispecific antibody with native IgG-like structure and phase 1 clinical trial is planned for the first quarter of 2022.

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.

Funding: Astellas Pharma Clinical Trial Registry Number: NCT03505320 Background: One accepted treatment for patients (pts) with advanced HER2-negative G/GEJ is mFOLFOX6 (5-FU, folinic acid, oxaliplatin)...Phase 2 results (NCT01630083, FAST) showed prolonged survival with zolbetuximab+EOX (epirubicin, oxaliplatin, capecitabine) vs EOX in G/GEJ... Results suggest promising antitumor activity with zolbetuximab+mFOLFOX6 in metastatic or locally advanced G/GEJ . The safety profile was manageable and no new safety signals were identified.