A large number of studies have shown that deglycosylation can enhance the antibody-dependent cytotoxic (ADCC) activity of monoclonal antibodies (mAbs), which has become an effective way to enhance the efficacy of therapeutic mAbs. This article evaluates the ADCC effect of trastuzumab and cetuximab (defucosylated and conventional mAbs). It has contributed a theoretical basis to the ADCC research of trastuzumab and cetuximab.
Trastuzumab
Trastuzumab consists of a covalent linkage of two drugs, the topoisomerase I inhibitor desretinacan and the humanized monoclonal antibody trastuzumab.
Fig.1 The structure of Trastuzumab. (Wikipedia)
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Mechanism of Trastuzumab
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Epidermal growth factor receptor 2 (ERBB2) mutations and nuclear localization
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Transcriptional alterations of ERBB2
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Post-translational alterations of ERBB2
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Over-activation of signaling pathways
Fig.2 Mechanisms of trastuzumab.2
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Cetuximab
As a recombinant chimeric human/mouse IgG1 monoclonal antibody. Cetuximab is an epidermal growth factor receptor (EGFR) inhibitor drug used to treat metastatic colorectal cancer and head and neck cancer.
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In July 2009, cetuximab (Erbitux) was approved for wild-type KRAS for colon cancer.
Fig.3 The structure of cetuximab. (Wikipedia)
1. Enhanced NK cell-mediated ADCC
2. Activate the link between natural killer cells (NK) and dendritic cells
3. Promote phagocytosis of cancer cells by dendritic cells
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Method
This study measured ADCC using peripheral blood mononuclear cells (PBMCs) from gastrointestinal cancers and healthy volunteers as target and effector cells, respectively.
Results
Fig.4 Determination of deglycosylated mAbs concentration.1
Fig.5 Determination of NK cell activity.1
Fig.6 ADCC effect of deglycosylated cetuximab and trastuzumab.1
Fig.7 Application of deglycosylated cetuximab and trastuzumab-mediated ADCC.1
Fig.8 ADCC is induced by deglycosylated cetuximab and trastuzumab under MAPK inhibitor therapy.1
Conclusion
This study suggests that defucosylated therapeutic mAbs enhance ADCC activity in cancer patients, which may lead to more effective anti-cancer therapies.
As a team with in-depth research in the field of ADCC, Creative Biolabs also has unique insights into the defucosylation of antibodies, please click here to view the Defucosylated Antibodies Engineering Service unit for more information. If you have any needs regarding ADCC development, please contact us now! scientists at Creative Biolabs are always here to provide you with professional advice and solutions!
References
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Nakajima, T.; et al.Augmentation of antibody-dependent cellular cytotoxicity with defucosylated monoclonal antibodies in patients with GI-tract cancer. Oncology letters. 2018, 15(2):2604-2610.
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Wang, Z.H.; et al. Trastuzumab resistance in HER2-positive breast cancer: Mechanisms, emerging biomarkers and targeting agents. Frontiers in oncology. 2022, 12: 1006429.
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