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Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
Published on: April 26, 2024
Inhibitory monoclonal antibody targeting ADAM17 expressed on cancer cells
Nayanendu Saha1, Kai Xu2, Zhongyu Zhu3
1Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States.
Abstract:
ADAM17 is upregulated in many cancers and in turn activates signaling pathways, including EGFR/ErbB, as well as those underlying resistance to targeted anti-EGFR therapies. Due to its central role in oncogenic pathways and drug resistance mechanisms, specific and efficacious monoclonal antibodies against ADAM17 could be useful for a broad patient population with solid tumors. Hence, we describe here an inhibitory anti-ADAM17 monoclonal antibody, named D8P1C1, that preferentially recognizes ADAM17 on cancer cells. D8P1C1 inhibits the catalytic activity of ADAM17 in a fluorescence-based peptide cleavage assay, as well as the proliferation of a range of cancer cell lines, including breast, ovarian, glioma, colon and the lung adenocarcinoma. In mouse models of triple-negative breast cancer and ovarian cancer, treatment with the mAb results in 78% and 45% tumor growth inhibition, respectively. Negative staining electron microscopy analysis of the ADAM17 ectodomain in complex with D8P1C1 reveals that the mAb binds the ADAM17 protease domain, consistent with its ability to inhibit the ADAM17 catalytic activity. Collectively, our results demonstrate the therapeutic potential of the D8P1C1 mAb to treat solid tumors.
Insights
A novel antibody, D8P1C1, targets ADAM17 (a key protein in cancer growth and drug resistance). This antibody effectively inhibits cancer cell proliferation and reduces tumor growth in preclinical models, showing promise for solid tumor treatment.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- ADAM17 (a disintegrin and metalloproteinase domain-17) is frequently upregulated in various cancers.
- ADAM17 activation drives oncogenic signaling pathways, including EGFR/ErbB.
- It also contributes to resistance mechanisms against targeted anti-EGFR therapies.
Purpose of the Study:
- To develop and characterize a specific monoclonal antibody (mAb) targeting ADAM17.
- To evaluate the therapeutic potential of the anti-ADAM17 mAb, D8P1C1, in preclinical cancer models.
Main Methods:
- Development of an inhibitory anti-ADAM17 monoclonal antibody, D8P1C1.
- In vitro assessment of D8P1C1's inhibitory activity using fluorescence-based peptide cleavage assays and cancer cell line proliferation assays.
- In vivo efficacy studies in mouse models of triple-negative breast cancer and ovarian cancer.
- Structural analysis using negative staining electron microscopy to determine the binding site of D8P1C1 on ADAM17.
Main Results:
- D8P1C1 effectively inhibits ADAM17's catalytic activity in vitro.
- D8P1C1 demonstrates significant inhibition of proliferation across multiple cancer cell lines (breast, ovarian, glioma, colon, lung adenocarcinoma).
- Treatment with D8P1C1 resulted in substantial tumor growth inhibition: 78% in triple-negative breast cancer models and 45% in ovarian cancer models.
- Electron microscopy confirmed D8P1C1 binds to the protease domain of ADAM17.
Conclusions:
- The D8P1C1 monoclonal antibody is a potent inhibitor of ADAM17 catalytic activity.
- D8P1C1 exhibits significant anti-tumor efficacy in preclinical models of solid tumors.
- These findings highlight the therapeutic potential of D8P1C1 for treating a broad range of solid tumors.
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