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Trispecific anti-CLDN-18.2/CD3/CD28 antibodies for gastric cancer treatment
Donaciano Flores-Robles1, Antonio Celestino Montes1, Jorge Antonio Perez Saldaña1
1Centro de Investigaciones Microbiológicas, Universidad Autónoma de Guerrero, Guerrero, México.
Abstract:
Claudin-18.2 is an overexpressed molecule in gastric cancer, which is why it is considered a potential therapeutic target. WO2024082060 describes trispecific antibodies directed against CDLN-18.2/CD3/CD28, and gastric cancer treatment method. These antibodies exhibit cytotoxic activity, in coculture with primary human CD3+ T lymphocytes, against gastric cancer cells expressing CLDN-18.2, as well as an inhibition of tumor growth rate in a murine model of gastric cancer. The trispecific structure, in particular the CD3 and CD28 binding domains, induce optimal co-stimulation of effector T cells, suggesting that these antibodies are potential candidates for clinical trials for the treatment of gastric cancer associated with high levels of CDLN-18.2 expression.
Insights
Trispecific antibodies targeting Claudin-18.2 (CLDN-18.2) show promise for gastric cancer treatment. These antibodies demonstrate cytotoxic activity against cancer cells and inhibit tumor growth, suggesting potential for clinical trials.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Claudin-18.2 (CLDN-18.2) is significantly overexpressed in gastric cancer, identifying it as a critical therapeutic target.
- Current therapeutic strategies for gastric cancer require novel approaches to improve patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of novel trispecific antibodies targeting CLDN-18.2, CD3, and CD28 for gastric cancer treatment.
- To assess the potential of these antibodies in preclinical models.
Main Methods:
- Development of trispecific antibodies binding to CLDN-18.2, CD3, and CD28.
- In vitro assessment of antibody-mediated cytotoxicity against CLDN-18.2-expressing gastric cancer cells using primary human CD3+ T lymphocytes.
- In vivo evaluation of tumor growth inhibition in a murine model of gastric cancer.
Main Results:
- The trispecific antibodies demonstrated significant cytotoxic activity against CLDN-18.2-positive gastric cancer cells in co-culture with T lymphocytes.
- A notable inhibition of tumor growth rate was observed in the murine gastric cancer model.
- The CD3 and CD28 binding domains of the antibodies were found to induce optimal co-stimulation of effector T cells.
Conclusions:
- Trispecific antibodies targeting CLDN-18.2, CD3, and CD28 are effective in preclinical models of gastric cancer.
- These antibodies exhibit potent anti-tumor activity through T-cell mediated cytotoxicity and co-stimulation.
- The findings support the advancement of these trispecific antibodies into clinical trials for gastric cancer patients with high CLDN-18.2 expression.
