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Published on: November 2, 2014
Elucidating Novel Targets for Ovarian Cancer Antibody-Drug Conjugate Development: Integrating In Silico Prediction
Emenike Kenechi Onyido1, David James1, Jezabel Garcia-Parra1
1Reproductive Biology and Gynaecological Oncology Group, Swansea University Medical School, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
Abstract:
Antibody-drug conjugates (ADCs) constitute a rapidly expanding category of biopharmaceuticals that are reshaping the landscape of targeted chemotherapy. The meticulous process of selecting therapeutic targets, aided by specific monoclonal antibodies' high specificity for binding to designated antigenic epitopes, is pivotal in ADC research and development. Despite ADCs' intrinsic ability to differentiate between healthy and cancerous cells, developmental challenges persist. In this study, we present a rationalized pipeline encompassing the initial phases of the ADC development, including target identification and validation. Leveraging an in-house, computationally constructed ADC target database, termed ADC Target Vault, we identified a set of novel ovarian cancer targets. We effectively demonstrate the efficacy of Surface Plasmon Resonance (SPR) technology and in vitro models as predictive tools, expediting the selection and validation of targets as ADC candidates for ovarian cancer therapy. Our analysis reveals three novel robust antibody/target pairs with strong binding and favourable antibody internalization rates in both wild-type and cisplatin-resistant ovarian cancer cell lines. This approach enhances ADC development and offers a comprehensive method for assessing target/antibody combinations and pre-payload conjugation biological activity. Additionally, the strategy establishes a robust platform for high-throughput screening of potential ovarian cancer ADC targets, an approach that is equally applicable to other cancer types.
Insights
This study introduces a new pipeline for developing antibody-drug conjugates (ADCs) for ovarian cancer. Researchers identified novel targets and validated promising antibody-drug conjugate candidates using advanced screening methods.
Area of Science:
- Biopharmaceuticals
- Oncology
- Drug Development
Background:
- Antibody-drug conjugates (ADCs) are a key advancement in targeted chemotherapy.
- Selecting specific targets is crucial for ADC efficacy in differentiating cancer cells from healthy ones.
- Challenges remain in the development of effective ADCs.
Purpose of the Study:
- To present a rationalized pipeline for early-stage ADC development, focusing on target identification and validation.
- To identify novel ovarian cancer targets using a computational database.
- To demonstrate the utility of Surface Plasmon Resonance (SPR) and in vitro models in expediting target selection.
Main Methods:
- Utilized an in-house ADC target database (ADC Target Vault) for target identification.
- Employed Surface Plasmon Resonance (SPR) technology for binding analysis.
- Validated antibody/target pairs using in vitro models with ovarian cancer cell lines.
Main Results:
- Identified novel targets for ovarian cancer therapy.
- Demonstrated three robust antibody/target pairs with strong binding affinity.
- Confirmed favorable antibody internalization rates in both wild-type and cisplatin-resistant ovarian cancer cells.
Conclusions:
- The developed pipeline enhances ADC development by providing a comprehensive method for assessing target/antibody combinations.
- The strategy offers a robust platform for high-throughput screening of potential ADC targets in ovarian cancer and other cancer types.
