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High-Content Screening Assay for the Identification of Antibody-Dependent Cellular Cytotoxicity Modifying Compounds
Published on: August 18, 2023
A novel HER2-targeting antibody 5G9 identified by large-scale trastuzumab-based screening exhibits potent synergistic
Xiaoyu Ding1, Wanjian Gu2, Yujie Zhong1
1Department of Clinical Laboratory, Jinling Hospital, State Key Laboratory of Analytical Chemistry for Life Science, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
Background:
Pertuzumab is currently used in combination with trastuzumab as the first-line treatment for HER2-positive metastatic breast cancer. However, pertuzumab was originally developed independently from trastuzumab and was later incidentally found to have synergistic efficacy when combined with trastuzumab, it remains to be seen whether a more potent synergistic efficacy partner exists for trastuzumab.
Methods:
A trastuzumab-based functional assay was used to screen anti-HER2 antibodies harboring trastuzumab-synergistic antitumor activity. The lead candidate 5G9, in combination with trastuzumab, was further characterized for its bioactivities in cell proliferation, cell apoptosis, antigen-antibody endocytosis and HER2-mediated cell signaling pathway blocking. Finally, animal models were used to evaluate the in vivo synergistic antitumor efficacy of 5G9 in combination with trastuzumab.
Findings:
Compared to pertuzumab, 5G9 demonstrated more potent synergistic cell growth inhibitory activity when combined with trastuzumab (85% vs. 55%, P<0.001). In addition, 5G9 exhibited a higher internalization rate than pertuzumab (20% vs. 9%, P<0.05), and was able to further synergize with trastuzumab to promote antigen-antibody endocytosis. The internalization rate of the combination of 5G9 and trastuzumab was higher than that of pertuzumab and trastuzumab (35% vs. 14%, P<0.001). In vivo animal studies demonstrated that 5G9 in combination with trastuzumab showed more potent synergistic antitumor efficacy than the combination of pertuzumab and trastuzumab.
Interpretation:
5G9, together with trastuzumab, may provide a potential opportunity for more efficacious treatment of HER2-positive cancers.
Funding:
National Natural Science Foundation of China; State Key Laboratory of Analytical Chemistry for Life Science.
Insights
A new antibody, 5G9, shows greater synergy with trastuzumab than pertuzumab for treating HER2-positive cancers. This combination offers a potentially more effective therapeutic option for patients with HER2-positive cancers.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Trastuzumab and pertuzumab are standard first-line treatments for HER2-positive metastatic breast cancer.
- Pertuzumab's synergy with trastuzumab was discovered serendipitously, prompting research for potentially more effective partners.
- The existence of a superior synergistic partner for trastuzumab remains an open question in HER2-positive cancer therapy.
Purpose of the Study:
- To identify and characterize novel anti-HER2 antibodies with synergistic antitumor activity when combined with trastuzumab.
- To evaluate the efficacy of a lead candidate antibody, 5G9, in preclinical models of HER2-positive cancer.
- To compare the synergistic potential of 5G9 with trastuzumab against that of pertuzumab with trastuzumab.
Main Methods:
- A functional assay based on trastuzumab was employed to screen for anti-HER2 antibodies exhibiting synergistic antitumor effects.
- The lead candidate, 5G9, was assessed for its impact on cell proliferation, apoptosis, and antigen-antibody endocytosis.
- In vivo studies using animal models were conducted to evaluate the combined antitumor efficacy of 5G9 and trastuzumab.
Main Results:
- 5G9 demonstrated significantly more potent synergistic cell growth inhibition with trastuzumab compared to pertuzumab (85% vs. 55%, P<0.001).
- 5G9 exhibited a higher internalization rate than pertuzumab, and its combination with trastuzumab led to enhanced antigen-antibody endocytosis (35% vs. 14%, P<0.001).
- In vivo studies confirmed that 5G9 plus trastuzumab yielded superior synergistic antitumor efficacy compared to pertuzumab plus trastuzumab.
Conclusions:
- The novel anti-HER2 antibody 5G9, in combination with trastuzumab, presents a promising therapeutic strategy for HER2-positive cancers.
- 5G9 offers a potential for more efficacious treatment outcomes in HER2-positive malignancies.
- Further clinical investigation of the 5G9-trastuzumab combination is warranted for HER2-positive cancer patients.
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