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

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.

• Authors: Yanyan Kong, Fang Xie, Zhengwei Zhang, Shaobo Wang, Yabin Zhang, Yang Di, Zhongwen Zhou, Donglang Jiang, Junpeng Li, Qi Huang, Jie Wang, Xiuming Li, Zhiwei Pan, Ruiqing Ni, Yihui Guan
• Journal: European radiology (Eur Radiol) Vol. 33 Issue 10 Pg. 7077-7088 (Oct 2023) ISSN: 1432-1084 [Electronic] Germany
• PMID: 37166496 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to European Society of Radiology.

Chemical References

• Radioisotopes

Topics

• Humans
• Pancreatic Neoplasms (diagnostic imaging, therapy, pathology)
• Adenocarcinoma (pathology)
• Tissue Distribution
• Carcinoma, Pancreatic Ductal (diagnostic imaging, therapy)
• Positron-Emission Tomography (methods)
• Radioisotopes (therapeutic use)
• Cell Line, Tumor
• Pancreatic Neoplasms