Herceptin/Trastuzumab for HER2-positive Breast Carcinoma

Trastuzumab

• Structure of Trastuzumab

Trastuzumab consists of a covalent linkage of two drugs, the topoisomerase I inhibitor desretinacan and the humanized monoclonal antibody trastuzumab.

Fig.1 Schematic diagram of ADCC

• Function of Trastuzumab

Trastuzumab binds to epidermal growth factor receptor 2 (HER2/neu) and blocks signaling in cancers that rely on it for growth.
After trastuzumab binds to the HER2 receptor, it interferes with the cell division process, causing cell DNA damage and destroying cells.

Mechanism of Trastuzumab

• ERBB2 mutations and nuclear localization
• Transcriptional alterations of ERBB2
• Post-translational alterations of ERBB2
• Over-activation of signaling pathways

Fig.2 Mechanisms of trastuzumab.

ADCC Effect of Trastuzumab

Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important mechanism for monoclonal antibody therapy for tumors and is independent of the HER2 signaling pathway. In vivo studies, trastuzumab had 96% inhibition of transplanted tumors in mice with normal ADCC effects. The grafted tumor inhibition rate in knockout mice lacking the ADCC gene (trastuzumab only plays an inhibitory role in the HER2 signaling pathway) was 29%. From this result, it can be seen that the ADCC mechanism plays a significantly greater role in trastuzumab treatment than the inhibition of the HER2 signaling pathway. Studies have also shown that trastuzumab-mediated ADCC is not affected by treatment timing, disease progression, and chemotherapy, and results support the use of trastuzumab in the treatment of all stages of breast cancer.

Fig.3 Trastuzumab-mediated ADCC effect in healthy people and patients.

Enhance the Efficacy of Trastuzumab

Improving the efficacy of trastuzumab focuses on enhancing the antitumor effect of ADCC, which is affected by many factors, such as IgGFc receptor polymorphism (the lack of activated receptor FcγRIIIa, FcγRIIa weakened ADCC effect), HER2 expression level (tumor cells with high expression of HER2 are more likely to cause ADCC effect), serum antibody level (IgG in serum competitively inhibits trastuzumab ADCC effect), cytokines and drugs (the glucocorticoid dexamethasone and the tumor necrosis factor antagonist thalidomide inhibit ADCC, serotonin receptor antagonist ondansetron and type II antihistamine receptor antagonist clomastine enhance ADCC effect). Current clinical applications focus on the usage of IL-2 to stimulate and activate effector cells involved in ADCC. Moreover, the taxel chemotherapy drugs paclitaxel and docetaxel also enhance trastuzumab ADCC effects.

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References

1. Wang, Z.H.; et al. Trastuzumab resistance in HER2-positive breast cancer: Mechanisms, emerging biomarkers and targeting agents. Frontiers in oncology. 2022, 12: 1006429.
2. Petricevic, B.; et al. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients. Journal of translational medicine. 2013, 11: 307.