CLDN18 and FGFR2 splicing variants are emerging tumor-associated antigens for cancer therapy

Alternative splicing and alternative promoters generate splicing variants to expand proteomic and transcriptional diversity to orchestrate physiological activities and dictate tumorigenesis. Splicing variants are attractive tumor-associated antigens (TAAs) for the clinical development of cancer therapies. Here, recent progress in claudin-18 isoform 2 (CLDN18.2)- and fibroblast growth factor receptor 2 isoform b (FGFR2b)-targeted therapeutics is summarized, and perspectives in this field are discussed. Zolbetuximab and bemarituzumab are first-generation monoclonal antibodies (mAbs) targeting CLDN18.2 and FGFR2b, respectively, while next-generation biologics targeting these TAAs are emerging. Single-agent objective response rates of CLDN18.2-targeting mAb (omectatug), antibody-drug conjugates (ADCs, arcotatug tavatecan, BL-M05D1, garetatug rezetecan, JS107, sonesitatug vedotin and tecotabart vedotin), bispecific antibodies (emaretamig and givastomig) and chimeric antigen receptor T (CAR-T) cells (IMC002) were higher than that of zolbetuximab. Gastrointestinal toxicity, nausea and vomiting are common on-target/off-tumor adverse effects of CLDN18.2-targeted biologics, which are mitigated for arcotatug tavatecan and givastomig as a result of antibody engineering. Combination therapy of zolbetuximab plus chemotherapy is approved for the treatment of gastric and gastroesophageal junction cancer patients, while results of other CLDN18.2-targeting biologics in phase 3 clinical trials are anticipated with expectations for improved clinical activities and mitigated adverse events. Diagnostics detecting alternative isoforms and combination strategies using immune checkpoint inhibitors would address resistance mechanisms, such as epitope-losing isoform switching and immune evasion. Comparative studies on ADC monotherapy versus combination mAb-chemotherapy as well as the clinical development of bispecific ADCs and allogeneic CAR-T cells should further improve the clinical benefits of CLDN18.2- and FGFR2b-targeted therapies.