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Published on: September 25, 2018
A CD276-Targeted Antibody-Drug Conjugate to Treat Non-Small Lung Cancer (NSCLC)
Jiashuai Zhang1, Zhuoxin Zora Zhou2, Kai Chen2
1Department of Biomedical Engineering, The Ohio State University (OSU), 151 West Woodruff Ave, Columbus, OH 43210, USA.
Abstract:
Non-small cell lung cancer (NSCLC) patients, accounting for approximately 85% of lung cancer cases, are usually diagnosed in advanced stages. Traditional surgical resection and radiotherapy have very limited clinical benefits. The objective of this study was to develop and evaluate a targeted therapy, antibody-drug conjugate (ADC), for NSCLC treatment. Specifically, the CD276 receptor was evaluated and confirmed as an ideal surface target of NSCLC in the immunohistochemistry (IHC) staining of seventy-three patient tumor microarrays and western blotting analysis of eight cell lines. Our anti-CD276 monoclonal antibody (mAb) with cross-activity to both human and mouse receptors showed high surface binding, effective drug delivery and tumor-specific targeting in flow cytometry, confocal microscopy, and in vivo imaging system analysis. The ADC constructed with our CD276 mAb and payload monomethyl auristatin F (MMAF) showed high anti-NSCLC cytotoxicity to multiple lines and effective anti-tumor efficacy in both immunocompromised and immunocompetent NSCLC xenograft mouse models. The brief mechanism study revealed the integration of cell proliferation inhibition and immune cell reactivation in tumor microenvironments. The toxicity study did not detect off-target immune toxicity or peripheral toxicity. Altogether, this study suggested that anti-CD276 ADC could be a promising candidate for NSCLC treatment.
Insights
A novel antibody-drug conjugate targeting CD276 shows promise for treating non-small cell lung cancer (NSCLC). This targeted therapy effectively kills NSCLC cells and reduces tumors with minimal toxicity.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) often presents at advanced stages with limited treatment options.
- Current therapies like surgery and radiotherapy offer minimal clinical benefit for advanced NSCLC.
Purpose of the Study:
- To develop and evaluate a targeted therapy, specifically an antibody-drug conjugate (ADC), for NSCLC treatment.
- To identify and validate CD276 as a suitable surface target for NSCLC therapy.
Main Methods:
- Immunohistochemistry (IHC) and western blotting were used to validate CD276 as an NSCLC target.
- An anti-CD276 monoclonal antibody (mAb) was developed and tested for binding and targeting capabilities.
- An ADC was constructed using the anti-CD276 mAb and monomethyl auristatin F (MMAF) payload for efficacy and toxicity studies.
Main Results:
- CD276 was confirmed as an ideal NSCLC surface target.
- The anti-CD276 mAb demonstrated high binding, drug delivery, and tumor-specific targeting.
- The anti-CD276 ADC exhibited potent anti-NSCLC cytotoxicity and significant anti-tumor efficacy in preclinical models.
- Mechanism studies indicated cell proliferation inhibition and immune cell reactivation.
- Toxicity studies showed no off-target immune or peripheral toxicity.
Conclusions:
- The anti-CD276 ADC is a promising therapeutic candidate for non-small cell lung cancer.
- Targeting CD276 offers a potential new strategy for NSCLC treatment with a favorable safety profile.
