Unlabelled

Despite their considerable advantages, many circulating biomarkers have well-documented limitations. One prominent shortcoming in oncology is a high frequency of false-positive indications for malignant disease in upfront diagnosis. Because one common cause of false positivism is biomarker production from benign disorders in unrelated host tissues, we hypothesized that probing the sites of biomarker secretion with an imaging tool could be a broadly useful strategy to deconvolute the meaning of foreboding but inconclusive circulating biomarker levels.

Methods

In preparation to address this hypothesis clinically, we developed (89)Zr-5B1, a fully human, antibody-based radiotracer targeting tumor-associated CA19.9 in the preclinical setting.

Results

(89)Zr-5B1 localized to multiple tumor models representing diseases with undetectable and supraphysiologic serum CA19.9 levels. Among these, (89)Zr-5B1 detected orthotopic models of pancreatic ductal adenocarcinoma, an elusive cancer for which the serum assay is measured in humans but with limited specificity in part because of the frequency of CA19.9 secretion from benign hepatic pathologies.

Conclusion

In this report, a general strategy to supplement some of the shortcomings of otherwise highly useful circulating biomarkers with immunoPET is described. To expedite the clinical validation of this model, a human monoclonal antibody to CA19.9 (a highly visible but partially flawed serum biomarker for several cancers) was radiolabeled and evaluated, and the compelling preclinical evidence suggests that the radiotracer may enhance the fidelity of diagnosis and staging of pancreatic ductal adenocarcinoma, a notoriously occult cancer.

Unlabelled

A noninvasive technology that indiscriminately detects tumor tissue in the brain could substantially enhance the management of primary or metastatic brain tumors. Although the documented molecular heterogeneity of diseases that initiate or eventually deposit in the brain may preclude identifying a single smoking-gun molecular biomarker, many classes of brain tumors are generally avid for transferrin. Therefore, we reasoned that applying a radiolabeled derivative of transferrin ((89)Zr-labeled transferrin) may be an effective strategy to more thoroughly identify tumor tissue in the brain, regardless of the tumor's genetic background.

Methods

Transferrin was radiolabeled with (89)Zr, and its properties with respect to human models of glioblastoma multiforme were studied in vivo.

Results

In this report, we show proof of concept that (89)Zr-labeled transferrin ((89)Zr-transferrin) localizes to genetically diverse models of glioblastoma multiforme in vivo. Moreover, we demonstrate that (89)Zr-transferrin can detect an orthotopic lesion with exceptional contrast. Finally, the tumor-to-brain contrast conferred by (89)Zr-transferrin vastly exceeded that observed with (18)F-FDG, currently the most widely used radiotracer to assess tumor burden in the brain.

Conclusion

The results from this study suggest that (89)Zr-transferrin could be a broadly applicable tool for identifying and monitoring tumors in the brain, with realistic potential for near-term clinical translation.

Purpose

The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics.

Experimental design

The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm³ or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant.

Results

⁸⁹Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n = 4/tumor). Treating mice with single or fractionated doses of ¹⁷⁷Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n = 8; P < 0.01). A single dose of ²²⁵Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with ¹⁷⁷Lu-4A06 (n = 8; P < 0.01). A significant survival advantage was imparted by ²²⁵Ac-4A06 (HR = 2.56; P < 0.05).

Conclusions

These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.