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Evaluation of novel anti-CEACAM6 antibody-based conjugates for radioimmunotheranostics of pancreatic ductal adenocarcinoma

  • Nuclear Medicine
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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor that lacks early diagnostic methods. Recently, targeted immunotherapy and radiotherapy have been integrated with radionuclide-antibody conjugate drugs, which can be used for targeted diagnosis and dynamic imaging of tumors. CEACAM6 is overexpressed in pancreatic tumors and is a potential theranostic target for PDAC. We aimed to develop a novel targeted carrier for theranostics of PDAC and other solid tumors.

Methods

Based on camelid heavy-chain-only antibodies, we developed a CEACAM6-targeting recombinant antibody NY004, and evaluated it as a novel antibody-carrier for imaging and therapy of cancer in tumor models. We labeled NY004 with theranostic nuclides and applied this self-developed antibody platform in diagnostic imaging and antitumor assessment in PDAC models.

Results

Through microPET, IHC, and biodistribution assays, targeting and biodistribution of [89Zr]-NY004 in solid tumors including PDAC was examined, and the investigated tumors were all CEACAM6-positive malignancies. We found that NY004 was suitable for use as a drug carrier for radioimmunotheranostics. Our study showed that NY004 was characterized by high targeted uptake and a long retention time in PANC-1 tumors (up to 6 days post-injection), with good specificity and high imaging efficiency. Therapeutic evaluation of the radionuclide-labeled antibody drug [177Lu]-NY004 in PDAC tumor-bearing model revealed that NY004 had high and prolonged uptake in tumors, relatively low non-target organ uptake, and good anti-tumor efficacy.

Conclusion

As a drug platform for radiotheranostics, CEACAM6-specific antibody NY004 met the requirements of easy-labeling, targeting specificity, and effective persistence in pancreatic adenocarcinoma tissues.

Key Points

• [89Zr]-NY004 has good specificity and high imaging efficiency, and is characterized by high tumor-targeting uptake and a long tumor retention time as a PET molecular imaging tracer.

• Therapeutic radionuclide-conjugated antibody drug [177Lu]-NY004 has high uptake and prolonged uptake duration in tumors, low non-target organ uptake, and significant tumor-inhibiting efficacy in PDAC model.

• The self-developed antibody structure NY004 is a promising drug platform for radioimmunotheranostics of CEACAM6-positive tumors including pancreatic ductal adenocarcinoma.

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Abbreviations

ADC:

Antibody-drug conjugate

CEA:

Carcinoembryonic antigen

CEACAM6:

Carcinoembryonic antigen–related cell adhesion molecule-6

ECM:

Extracellular matrix

Fc:

Crystallizable fragment

IHC:

Immuno-histochemical

PDAC:

Pancreatic ductal adenocarcinoma

RAC:

Radionuclide-antibody conjugate

RIT:

Radioimmuno-therapy

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Acknowledgements

We gratefully acknowledge Chi Lai Ho for reviewing the manuscript for critical comments.

Funding

This study has received funding from the Original Research Personalized Support Project, Fudan University (No. IDF151039/020), National Natural Science Foundation of China (No. 81701732, 82071962), Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01), and ZJLab, Shanghai Municipal Key Clinical Specialty (shslczdzk03402) and Clinical Research Plan of SHDC (No. SHDC2020CR2056B).

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Authors and Affiliations

  1. PET Center, Huashan Hospital, Fudan University, Shanghai, 200235, China

    Yanyan Kong, Fang Xie, Zhengwei Zhang, Donglang Jiang, Junpeng Li, Qi Huang, Jie Wang, Xiuming Li, Zhiwei Pan & Yihui Guan

  2. PET/CT Center, The First People’s Hospital of Yunnan Province, Kunming, 650032, Yunnan, China

    Shaobo Wang

  3. Department of Nuclear Medicine, Third People’s Hospital of Honghe State, Honghe, 661000, Yunnan, China

    Yabin Zhang

  4. Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Yang Di

  5. Department of Pathology, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Zhongwen Zhou

  6. Institute for Biomedical Engineering, ETH Zurich & University of Zurich, Zurich, Switzerland

    Ruiqing Ni

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  1. Yanyan Kong
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  2. Fang Xie
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Correspondence to Yanyan Kong, Ruiqing Ni or Yihui Guan.

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The scientific guarantor of this publication is Yihui Guan.

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The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article.

Statistics and biometry

Yanyan Kong kindly provided statistical advice for this manuscript. One of the authors has significant statistical expertise. No complex statistical methods were necessary for this paper.

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Approval from the institutional animal care committee was obtained.

Ethical approval

Institutional review board approval was obtained. All animal studies were performed in accordance with the guidelines of the Animal Welfare Office of Fudan University. The Institutional Animal Care and Use Committee of Fudan University reviewed and approved the experimental procedures. The animals were maintained under anesthesia during the model development, injection, accumulation, and scanning periods to avoid suffering at each stage of the experiment.

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Kong, Y., Xie, F., Zhang, Z. et al. Evaluation of novel anti-CEACAM6 antibody-based conjugates for radioimmunotheranostics of pancreatic ductal adenocarcinoma. Eur Radiol 33, 7077–7088 (2023). https://doi.org/10.1007/s00330-023-09679-w

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