Abstract 5206: IND enabling investigations of MVT-1075, a CA19-9 targeting radioimmunotherapy

Abstract Rationale: The CA19-9 antigen is overexpressed in pancreatic and other GI tumors. MVT-5873 (HuMab-5B1), a fully human monoclonal antibody currently in phase I study, targets the sialyl Lewis A (sLea) epitope on CA19-9, and is a promising platform for development of a targeted radioimmunotherapy (RIT). MVT-5873 was conjugated with the chelator CHX-A″-DTPA and radiolabeled with Lutetium-177 (177Lu) to form MVT-1075 (177Lu- CHX-A″-DTPA-HuMAb-5B1). We have completed IND enabling process development, stability, and characterization investigations and plan to initiate a phase I trial in patients with pancreatic cancer and other CA19-9 positive malignancies early in 2017. Methods: Reproducible conditions to conjugate the chelator (p-SCN-Bn-CHX-A˝-DTPA) to MVT-5873 were developed by evaluating chelator to antibody ratios and incubation times. The stability of MVT-1075 was assessed in formulation buffer at shipping/handling conditions, and in human serum via thin layer chromatography (iTLC), size exclusion chromatography (SEC) and ion-exchange chromatography (CEX). The immunoreactive fraction was determined at each time point using a microsphere based LINDMO method developed for this program. Results: MVT-5873 was buffer exchanged into 100mM sodium bicarbonate buffer at pH9 and combined with p-SCN-Bn-CHX-A˝-DTPA at 32.5°C for 90 min. Unincorporated chelator was removed by buffer exchange into 1M ammonium acetate buffer at pH7. The resulting conjugate, MVT-7814 (CHX-A˝-DTPA-HuMab-5B1), was characterized for degree and location of conjugation by MS, aggregates, ELISA binding, purity by CEX and pI determination. These analyses indicated a single CHX-A˝-DTPA on the heavy chain as the primary conjugate. In vitro binding by ELISA was comparable to MVT-5873. Purity by SEC was 99% showing minimal aggregation. MVT-7814 is stored frozen at <-60°C and stable to 5 freeze-thaw cycles. To qualify MVT-1075 for clinical use, MVT-7814 was radiolabeled with 177Lu. Purity data indicate a high degree (>98%) of 177Lu incorporation by iTLC and stability in formulation buffer up to 120 hours (< -15oC) and 24 hours ambient by immunoreactivity as assessed by a LINDMO method (> 90%) at both conditions. Serum stability at 37oC showed radiochemical purity >82% by iTLC and immunoreactivity >62% after 5 days, further supporting the use of this product in clinical trials. Conclusions: The conjugation of MVT-5873 with p-SCN-Bn-CHX-A˝-DTPA reproducibly yields a well characterized bulk intermediate (MVT-7814) modified on the heavy chain. Radiolabeling with 177Lu and stability studies in formulation buffer and human serum indicate that MVT-1075 maintains radiochemical purity and target immunoreactivity to support clinical use. The results of these studies were consistent with specifications and support the clinical utility and submission of the MVT-1075 IND application with an expected FIH date early in 2017. Citation Format: Dennis Gately, Marvin Peterson, Sara Dao, Scott Rudge, George St. George, Shannon Phillips, Paul Maffuid. IND enabling investigations of MVT-1075, a CA19-9 targeting radioimmunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5206. doi:10.1158/1538-7445.AM2017-5206