Abstract
Abstract Background: Sialyl Lewis A (sLea) modification occurs on transmembrane and secreted proteins in pancreatic ductal adenocarcinoma (PDAC) and other GI cancers, leading to a high level of expression on cancer cells compared to normal tissue. sLea, also known as CA19-9, can be detected in patient serum using a CA19-9 diagnostic assay, which detects shed or secreted sLea modified proteins. MVT-5873, a fully human antibody that specifically targets the sLea antigen, is in a phase 1 clinical trial for the treatment of CA19-9 positive disease as a monotherapy (MVT-5873), as an imaging agent (MVT-2163), and as a radioimmunotherapy (MVT-1075). Methods: To understand the relevance of CA19-9 as a stratification marker, both annotated primary as well as patient-derived xenograft (PDX) tissue microarrays (TMAs) were stained with MVT-5873. To evaluate sLea as a response biomarker, serum samples from patients in the MVT-5873 phase 1 clinical trial were analyzed for CA19-9 levels using the diagnostic assay, and compared to their MVT-5873 PK profile. Available samples were also characterized by ELISA assay to determine the representation of sLea modification on MUC family proteins. Results: For the human CRC TMA, >75% of tumor cores displayed moderate to high levels of positive staining. In the PDX array, 21% of non-small cell lung cancer (NSCLC), 50% of small cell lung cancer (SCLC), and 69% of CRC cores stained positive. Overall, staining was observed with similar frequency regardless of mutational status of the tumor, suggesting that CA19-9 expression is independent of KRAS, BRAF, PIK3CA, or MMR pathway mutations. Staining was also relatively unchanged in lung PDX cancer tumor cores that were rendered chemoresistant compared to their chemosensitive precursor. The serum CA19-9 analysis of PDAC patients treated with MVT-5873 demonstrated that detectable CA19-9 is inversely proportional to MVT-5873 drug levels when CA19-9 levels are >100 U/ml. CA19-9 is not detected after MVT-5873 treatment when CA19-9 levels are <100 U/ml, suggesting that MVT-5873 can fully occupy all serum CA19-9 at those levels. Taken together, these data indicate that the CA19-9 diagnostic assay may be used as a measure for target engagement, and imaging data from the MVT-2163 phase 1 trial confirmed that the drug can efficiently accumulate at tumor sites in a time-dependent manner in patients. When pancreatic cancer patient serum was analyzed for protein scaffold composition, Muc1 and Muc16 were found to be present. Conclusions: These data support the use of sLea targeted therapeutics such as MVT-5873 and MVT-1075 in CRC and lung cancer, including for patients with KRAS or other genetic lesions. Additionally, for patients treated with MVT-5873, data suggest that the serum CA19-9 assay is a potential measure of target occupancy and is worthy of further investigation. Citation Format: H. Toni Jun, Christian Lohrmann, Viola Allaj, Wolfgang Scholz, G. Jonah Rainey, Wolfgang A. Weber, Jason S. Lewis, John Poirier, Paul W. Maffuid. Using CA19-9 as a translational biomarker for sLea targeted agents MVT-5873 and MVT-1075 in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A062.
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