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Published on: January 19, 2019
Antitumor effect of an antibody against gastrointestinal cancer-associated antigen CA19.9
Zheng Li1, Xueli Liu, Yunxia Wan
1State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, PUMC, Beijing, China.
Abstract:
Despite tremendous efforts in developing cancer vaccines and monoclonal antibodies (mAbs), only a few passive or active immunotherapeutic modalities have succeeded. The failure may be due to the existence of immunosuppressive factors, which caused anergy of patients' immune system. In this study, we discovered that CA19.9 is one such immunosuppressive factor, which could inhibit the proliferation of activated human lymphocytes. However, this inhibition could be reversed by a mAb, LC44, which was specifically generated against CA19.9. An in vitro cytotoxic experiment showed that mAb LC44 could form an immunocomplex with CA19.9, which subsequently induced the production of cytotoxic T-cells reacting to CA19.9-positive cancer cells. In addition, mAb LC44 could mediate the complement-dependent cytotoxicity to CA19.9-positive cancer cells. mAb LC44 showed an antitumor effect in immunodeficient mice with colon cancer burden in the presence or absence of CA19.9. Based on the observations from this study, we postulated that the mAb, LC44, could be a promising antitumor agent for gastrointestinal cancer and worthy of further investigation.
Insights
This study identifies CA19.9 as an immunosuppressive factor in cancer. A novel monoclonal antibody (mAb), LC44, targeting CA19.9, demonstrated potential in reversing immunosuppression and exhibiting antitumor effects against gastrointestinal cancers.
Area of Science:
- Immunology
- Oncology
- Cancer Immunotherapy
Background:
- Cancer immunotherapy, including vaccines and monoclonal antibodies (mAbs), has limited success due to immunosuppressive factors causing immune anergy.
- CA19.9 has been identified as a novel immunosuppressive factor that inhibits activated human lymphocyte proliferation.
Purpose of the Study:
- To investigate the role of CA19.9 as an immunosuppressive factor in cancer.
- To evaluate the therapeutic potential of a newly developed monoclonal antibody (mAb) LC44, specifically targeting CA19.9, for cancer treatment.
Main Methods:
- In vitro studies involving lymphocyte proliferation assays and cytotoxic experiments.
- Assessment of mAb LC44's ability to form immunocomplexes with CA19.9.
- Evaluation of complement-dependent cytotoxicity mediated by mAb LC44.
- In vivo antitumor efficacy studies in immunodeficient mice bearing colon cancer.
Main Results:
- CA19.9 was confirmed to inhibit activated human lymphocyte proliferation.
- mAb LC44 effectively reversed the immunosuppressive effects of CA19.9.
- mAb LC44 induced cytotoxic T-cell production against CA19.9-positive cancer cells.
- mAb LC44 mediated complement-dependent cytotoxicity and demonstrated antitumor effects in a mouse model.
Conclusions:
- mAb LC44 shows promise as a therapeutic agent for gastrointestinal cancers by overcoming CA19.9-mediated immunosuppression.
- The dual mechanism of action, including immunocomplex formation and complement-dependent cytotoxicity, contributes to mAb LC44's antitumor activity.
- Further investigation of mAb LC44 is warranted for its clinical application in treating CA19.9-positive gastrointestinal malignancies.
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