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The target atlas for antibody-drug conjugates across solid cancers

Cancer Gene Therapy volume 31, pages 273–284 (2024)Cite this article

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Abstract

Antibody-Drug Conjugates (ADCs) represent a rapidly advancing category of oncology therapeutics, spanning the targeted therapy for both hematologic malignancies and solid cancers. A crucial aspect of ADC research involves the identification of optimal surface antigens that can effectively differentiate target cells from most mammalian cell types. Herein, we have devised an algorithm and compiled an extensive dataset annotating cell membrane proteins. This dataset is derived from comprehensive transcriptomic, proteomic, and genomic data encompassing 19 types of solid cancer as well as normal tissues. The aim is to uncover potential therapeutic surface antigens for precise ADC targeting. The resulting target landscape comprises 165 combinations of targets and indications, along with 75 candidates of cell surface proteins. Notably, 35 of these candidates possess characteristics suitable for ADC targeting, and have not been previously reported in ADC research and development. Additionally, we have identified a total of 159 ADCs from a pool of 760 clinical trials. Of these, 72 ADCs are presently undergoing interventional evaluation for a variety of solid cancer types, targeting 36 unique antigens. We conducted an analysis of their expression in normal tissues using this comprehensive annotation dataset, revealing a diverse range of profiles for the current ADC targets. Moreover, we emphasize that the biological impacts of target antigens have the potential to enhance their clinical effectiveness. We propose a comprehensive assessment of the drugability of target antigens, considering multiple facets. This study represents a thorough exploration of pan-cancer ADC targets over the past two decades, underscoring the potential of a comprehensive solid cancer target atlas to broaden the scope of ADC therapies.

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Fig. 1: Expression profile and differential expression profile of ADC targets and overview of the clinical development pipelines and current ADC targets.
Fig. 2: Expression profile and differential expression profile of selected target antigens screened from the algorithm.
Fig. 3: Circular visualization of the differential gene expression profile of target antigens in normal tissues.
Fig. 4: Heterogeneous gene expression pattern of several target candidates.
Fig. 5: Predicted target overexpression analysed by functional genomic mRNA profiling.
Fig. 6: The common genetic alterations of oncogenes and a combinatorial analysis of their coding protein as ADC targets.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability

The custom computer codes utilized during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors. The authors thank Dr. Simon Wang at the Language Centre, HKBU, for help with an improvement to the linguistic presentations of the manuscript.

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Authors and Affiliations

  1. Interdisciplinary Institute of Medical Engineering, Fuzhou University, Fuzhou, Fujian, 350108, China

    Jiacheng Fang & Lei Guo

  2. State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, RRS812, Kowloon Tong, Hong Kong SAR, China

    Jiacheng Fang & Xiaoxiao Wang

  3. School of Ecology and Environment, Zhengzhou University, Zhengzhou, Henan, 450001, China

    Yanhao Zhang

  4. Department of Chemistry, Hong Kong Baptist University, RRS812 Kowloon Tong, Hong Kong SAR, China

    Qing Guo

  5. College of Food Science & Engineering, Northwest University, 229 Taibai North Road, Xi’an, Shaanxi, 710069, China

    Ming Wang

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Contributions

JF: conceptualization, investigation, methodology, data curation, data visualization, writing—original draft, writing—review and editing; LG: supervision, project administration, funding acquisition; YZ: investigation, methodology, software; QG: data curation, software; MW, XW: supervision, methodology, project administration.

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Correspondence to Lei Guo, Ming Wang or Xiaoxiao Wang.

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Fang, J., Guo, L., Zhang, Y. et al. The target atlas for antibody-drug conjugates across solid cancers. Cancer Gene Ther 31, 273–284 (2024). https://doi.org/10.1038/s41417-023-00701-3

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