Abstract A73: Antitumor activity of MVT-5873, a monoclonal antibody targeting sialyl Lewisa, alone and in combination with gemcitabine/nab-paclitaxel in a BxPC3 human pancreatic cancer xenograft model

Abstract

Introduction: MVT-5873 (HuMab-5B1) is a fully human monoclonal antibody that specifically targets the sialyl Lewis A (sLea) epitope on CA19-9, a carbohydrate antigen frequently overexpressed in pancreatic and other gastrointestinal malignancies. The antitumor activity of MVT-5873 as a single agent and in combination with gemcitabine (Gem) + nab-paclitaxel (nab-P, Abraxane®), a standard of care combination for pancreatic cancer, was evaluated in SCID mice bearing subcutaneous BxPC3 human pancreatic cancer tumor xenografts, known to express CA19-9.

Methods: Treatment was initiated on Day 9 after BxPC3 cell inoculation; mean tumor volume having reached 150 mm3. Groups of mice (n= 5) were given MVT-5873 at dose levels of 5, 15, and 30 mg/kg alone or with Gem 80 mg/kg + nab-P 20 mg/kg intraperitoneally 2x/week for 5 weeks. Control groups received human IgG 30 mg/kg, Gem/nab-P, or saline on the same schedule. Tumor volumes were measured 2x/week through Day 41, trough (C_min) serum samples for MVT-5873 pharmacokinetic (PK) analysis were obtained Days 13, 16, 23, 30, 37, & 44. Tumor tissue samples for IHC analysis were obtained upon study termination, Day 44.

Results: Day 41 tumor volumes were substantially reduced with single-agent MVT-5873 at doses of 5, 15, and 30 mg/kg, with relative mean volumes of 68%, 76%, and 64%, respectively, that of IgG control. Combination of Gem/nab-P with MVT-5873 at 5, 15, or 30 mg/kg further enhanced activity, resulting relative tumor volumes of 39%, 32%, and 31%, respectively, that of IgG control (p <.01 for all). Using Gem/nab-P as comparative baseline, relative Day 41 tumor volumes were 82%, 67%, and 65%, respectively, with MVT-5873 at 5, 15, or 30 mg/kg + Gem/nab-P (p <.05 for the 15 and 30 mg/kg groups). Tumor Growth Inhibition (TGI) Index values for single-agent MVT-5873 at 5, 15, and 30 mg/kg were 37%, 28%, and 42%, respectively, while combinations of MVT-5873 at 5, 15, and 30 mg/kg with Gem/nab-P produced TGI values of 71%, 80%, and 81%, respectively. Time to 50% tumor growth increased approximately 2-fold across all MVT-5873 + Gem/nab-P groups. Serial MVT-5873 C_min PK values remained relatively constant in the absence of tumor but declined over time in tumor-bearing animals, with an inverse relationship between serum concentrations and tumor volume suggested. IHC analysis of tumor-associated MVT-5873 antibody showed intensified uptake relative to MVT-5873 dose and an indication of higher tumor uptake with the addition of chemotherapy.

Conclusions: MVT-5873 demonstrates antitumor activity as a single agent and enhances the activity of Gem/nab-P chemotherapy in a BxPC3 human pancreatic xenograft model. These findings support the current Phase I clinical investigation of MVT-5873 as a single agent and in combination with Gem/nab-P in patients with advanced pancreatic cancer and other CA19-9 positive malignancies. (NCT02672917)

Citation Format: Govind Ragupathi, Xiaohong Wu, Philip Livingston, Wolfgang Scholz, Christine Kearns, Paul Maffuid.{Authors}. Antitumor activity of MVT-5873, a monoclonal antibody targeting sialyl Lewisa, alone and in combination with gemcitabine/nab-paclitaxel in a BxPC3 human pancreatic cancer xenograft model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A73.