Abstract 3664: CDX-1402, a dendritic cell targeted fusion protein designed to elicit immunity to mesothelin and HER2 expressing tumors
Authors: He Li-Zhen , Widger Jenifer , Testa James , Mills-Chen Laura , Zhao Biwei , Weidlick Jeff , Sisson Crystal , Wasiuk Anna , Vitale Laura , Goldstein Joel , Marsh Henry , Keler Tibor , Ramakrishna Venky 
Published: July 2017

Abstract
The use of mAbs to target antigens to the endocytic receptor Dec205 on dendritic cells (DC) is an effective means to elicit helper and cytolytic T cell responses in the presence of appropriate adjuvants to activate DC. We have translated this concept to clinical studies using a fully human Dec205-specific mAb genetically altered to include the entire NY-ESO-1 cancer antigen (CDX-1401), which when combined with TLR agonists results in effective stimulation of both cellular and humoral NY-ESO-1-specific responses in cancer patients (Dhodapkar MV et al., Sci. Transl. Med. 6:232-251, 2014). Building on this concept, we developed a new fusion protein in which the Dec205 mAb is engineered to carry two tumor-related antigens in tandem [ECDs of mesothelin (MSLN) and HER2]. HER2 and MSLN are broadly expressed in selected tumor types and provide an expanded opportunity for this immunotherapy approach. We previously generated an anti-mouse DC-targeted HER2 vaccine (αDec205-HER2) and a MSLN vaccine (αDec205-MSLN) and demonstrated in mouse studies that they were potent in eliciting strong and broad CD4 T cell immunity, cross priming of CD8 T cells and humoral responses specific for HER2 or MSLN antigens, respectively. In this work we tested the impact of expressing two tumor antigens in the same construct on the immune responses to each antigen. Mice of various genetic backgrounds were immunized with equimolar amount of αDec205-HER2 (6.8 μg), αDec205-MSLN (5 μg) or αDec205-MSLN-HER2 (8.3 μg) in combination with poly IC-LC plus anti-CD40 or anti-CD27 as adjuvant. Similar levels of CD4 and CD8 T cell responses upon single or dual antigen vaccination were observed in the assessment of intracellular cytokines and IFNγ-ELISPOT after ex vivo stimulation with peptide pools derived from either HER2 or MSLN. High titers of anti-HER2 and anti-MSLN IgG, including IgG1 and IgG2a, were elicited upon αDec205-MSLN-HER2 vaccination. Both humoral and cellular responses were boosted by multiple dosing of the vaccine. Based on these data we developed CDX-1402 using our anti-human Dec205 mAb genetically fused to MSLN and HER2. CDX-1402 was shown to effectively deliver these antigens to human DC in vitro for activation of antigen-specific T cells. In vitro stimulation of healthy volunteer circulating T cells with autologous DC treated with CDX-1402 plus TLR agonist resulted in T cell cultures that produced IFNγ only when presented with CDX-1402-treated DCs or DC loaded with a select panel of HLA-I/II synthetic peptides derived from either MSLN or HER2 but not with control peptides. We also observed that T cells sensitized to CDX-1402 recognize cancer cell lines that express the vaccine antigen and HLA. Altogether, the data lend support for the use of CDX-1402 as a novel immunotherapeutic for treatment of multiple cancer types expressing MSLN and/or HER2.
Citation Format: Li-Zhen He, Jenifer Widger, James Testa, Laura Mills-Chen, Biwei Zhao, Jeff Weidlick, Crystal Sisson, Anna Wasiuk, Laura Vitale, Joel Goldstein, Henry Marsh, Tibor Keler, Venky Ramakrishna. CDX-1402, a dendritic cell targeted fusion protein designed to elicit immunity to mesothelin and HER2 expressing tumors [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 3664. doi:10.1158/1538-7445.AM2017-3664