Abstract 2392: CDX-527: A novel bispecific immune-modulating antibody targeting CD27 and PD-L1
Authors: Vitale Laura A. , Thomas Lawrence J. , O'Neill Thomas , Widger Jenifer , Mills-Chen Laura , Crocker Andrea , Patterson Colleen , Wasiuk Anna , Forsberg Eric , Boyer James , Sisson Crystal , Weidlick Jeffrey , Renn-Bingham Shannon , Papayannopoulos Ioannis , Hammond Russ , Goldstein Joel , Marsh Henry C. , Keler Tibor , He Li-Zhen 
Published: August 2019

Abstract
CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 axis on T cells. Combining a CD27 agonist monoclonal antibody (mAb) with PD-1/PD-L1 blockade has been shown to promote synergistic antitumor activity in preclinical models. In advanced cancer patients, the combination of the CD27 agonist mAb, varlilumab, with the PD-1 mAb, nivolumab, was generally well tolerated, induced strong biological effects, and led to sustained clinical responses in some patients that generally have low response rates to checkpoint inhibitors. We theorized that combining CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (bsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by crosslinking through PD-L1 in addition to Fc receptors. To test this approach, we developed CDX-527, a tetravalent human anti-CD27/PD-L1 IgG1 bsAb. CDX-527 inhibits PD-1 signaling in vitro in a manner similar to clinically approved PD-1/PD-L1 antibodies. CDX-527 also elicits potent T cell costimulation through PD-L1 crosslinking as measured by cytokine induction and cell proliferation, whereas the PD-L1 or CD27 parental antibodies show no significant activity. In a mixed lymphocyte reaction assay, CDX-527 is more potent than the combination of the parental antibodies, suggesting that cross-linking through both Fc receptors and PD-L1 results in enhanced CD27 agonist activity. In human CD27 transgenic mice, we observed that antigen-specific T cell responses to a vaccine in vivo are significantly more enhanced with a surrogate CD27/PD-L1 bsAb than with either individual antibody. Furthermore, the surrogate bsAb exhibits greater antitumor activity than the combination of the parental antibodies in a syngeneic lymphoma model. Taken together, these results suggest that the enhanced activity of CDX-527 can be attributed to more efficient cross-linking of the bispecific antibody acting on the CD27 receptor, resulting in stronger T cell activation, combined with efficient PD-1/PD-L1 blockade, providing a novel approach to immunotherapy of cancers. We have initiated development activities for CDX-527 including a pilot study in cynomolgus macaques to investigate the PK and PD properties and provide guidance for the design of a GLP toxicology study.
Citation Format: Laura A. Vitale, Lawrence J. Thomas, Thomas O'Neill, Jenifer Widger, Laura Mills-Chen, Andrea Crocker, Colleen Patterson, Anna Wasiuk, Eric Forsberg, James Boyer, Crystal Sisson, Jeffrey Weidlick, Shannon Renn-Bingham, Ioannis Papayannopoulos, Russ Hammond, Joel Goldstein, Henry C. Marsh, Tibor Keler, Li-Zhen He. CDX-527: A novel bispecific immune-modulating antibody targeting CD27 and PD-L1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2392.