Pancreatic cancer is a challenge to stage because there’s no good molecular imaging method – but three new antibody conjugates may change that
It’s well-known that one reason pancreatic cancer is so difficult to defeat is that it’s usually diagnosed in the late stages, after surgical resection – the only curative option – is no longer a possibility. But of the small fraction of patients who do qualify for surgery, less than one-fifth survive for five years or more (1). That’s because of the high incidence of undiscovered metastases. It’s difficult to accurately stage pancreatic ductal adenocarcinoma (PDAC), because no molecular imaging tools are up to the task. But that might soon change; a group of scientists at Memorial Sloan Kettering Cancer Center have described and evaluated three new immunoconjugates that can be used for positron emission tomography (PET) and near-infrared fluorescent (NIRF) optical imaging of PDAC tumors. To make the new imaging agents (2), researchers began with the human monoclonal antibody 5B1, which recognizes CA19.9 – the most highly expressed antigen in PDAC tumor tissue. To 5B1, they conjugated either desferrioxamine (DFO, which enables radiolabeling with 89Zr for PET imaging), a fluorophore for NIRF imaging, or both. They used a site-specific strategy that involves affixing molecules via the heavy chain glycans of the antibody (see Figure 1), which produces well-defined, robust results and simplifies the development of dual-modal immunoconjugates.
The uptake of the antibodies was exceptional both in vitro and in vivo, particularly in the case of the dual construct – and they were retained much better in tumor than in non-target tissue. When applied to a mouse model of PDAC, the conjugates provided a clear image of the malignancy, including NIRF-visualized abdominal micrometastases that couldn’t be seen by the naked eye or in PET imaging. These are only early steps toward a better way of imaging pancreatic cancer. Further studies need to be conducted – first in a better mouse model that constitutively expresses CA19.9, and then, if successful, in clinical trials.
The uptake of the antibodies was exceptional both in vitro and in vivo, particularly in the case of the dual construct – and they were retained much better in tumor than in non-target tissue. When applied to a mouse model of PDAC, the conjugates provided a clear image of the malignancy, including NIRF-visualized abdominal micrometastases that couldn’t be seen by the naked eye or in PET imaging. These are only early steps toward a better way of imaging pancreatic cancer. Further studies need to be conducted – first in a better mouse model that constitutively expresses CA19.9, and then, if successful, in clinical trials.
But if the new immunoconjugates work as well in future studies as they have to date, doctors may eventually be able to gain a clearer picture of a tumor’s invasiveness, leading to better staging and, of course, more targeted treatment.
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References
- JL Cameron et al., “One thousand consecutive pancreaticoduodenectomies”, Ann Surg, 244, 10–15 (2006). PMID: 16794383. JL Houghton et al., “Site-specifically labeled CA19.9-targeted immunoconjugates for the PET, NIRF, and multimodal PET/NIRF imaging of pancreatic cancer”, Proc Natl Acad Sci USA, [Epub ahead of print] (2015).