Abstract 4550: CD80 vIgD-Fc proteins combine checkpoint antagonism and costimulatory signaling for potent antitumor immunity
2018
Introduction: PD-1 pathway antagonists have revealed the importance of checkpoint pathways in regulating antitumor immunity, but an existing immune response is generally required for clinical efficacy. Specific T cell costimulation through
CD28is central to this process, but the
CD28ligands
CD80and
CD86are often poorly expressed in the tumor microenvironment, accounting for a second important mechanism of immune evasion by tumors. In contrast,
PD-L1expression has been found extensively in multiple tumor cell types. Therapeutics that combine
PD-L1/PD-1 antagonism coupled with
PD-L1dependent
CD28
agonismmay therefore provide a more potent, yet safe immunotherapeutic approach. Experimental Procedures: The variant Ig Domain (vIgD) TM platform has generated a diversity of human
CD80variants using
yeast display
affinity maturationand selections against all three
CD80counterstructures
CD28,
CTLA-4, and
PD-L1.
CD80vIgDs were produced in a mammalian expression system as recombinant Fc fusion proteins (
CD80vIgD-Fc proteins) and their binding properties were quantified by flow cytometry. Functional activity was determined in vitro by assessing responses from human primary T cells or an IL-2-luciferase Jurkat T cell reporter line stimulated with
PD-L1-expressing
artificial antigen presenting cells(aAPCs). In vitro human T cell cytotoxicity assays with a human
PD-L1-expressing tumor line were also performed. Antitumor activity was assessed in vivo with mice implanted with human
PD-L1transduced MC38 tumors. Data Summary: The human
CD80IgV fragment was found to be optimal for high affinity
PD-L1and
CD28binding. A large panel of
CD80vIgD-Fc proteins demonstrated a range of binding towards
CD28,
PD-L1, and/or
CTLA-4, and
CD80vIgD-Fc proteins with high affinity for
PD-L1antagonized the
PD-L1/PD-1 interaction. Some
CD80vIgD-Fc proteins
agonized
CD28in a
PD-L1dependent fashion with increased luciferase activity in the Jurkat reporter assay as well as increased cytokine production by primary human T cells when stimulated with a
PD-L1expressing aAPC in vitro. The same candidates also showed specific killing of human
PD-L1expressing tumor cells in vitro compared to the parental tumor line lacking
PD-L1expression. Importantly, selected
CD80vIgD-Fc proteins caused significant tumor reduction in the MC38 in vivo tumor model. Conclusion: Engineered
CD80vIgD-Fc proteins that deliver a localized
CD28costimulatory signal to T cells while simultaneously antagonizing the inhibitory
PD-L1/PD-1 pathway may provide a transformative mechanism of action to drive potent, tolerable antitumor immunity. Preclinical development of therapeutic candidates is under way. Citation Format: Ryan Swanson, Mark F. Maurer, Chris L. Navas, Chelsea J. Gudgeon, Joseph L. Kuijper, Martin Wolfson, Katherine E. Lewis, Stacey R. Dillon, Steve D. Levin, Michael G. Kornacker.
CD80vIgD-Fc
proteins combinecheckpoint antagonism and costimulatory signaling for potent antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4550.
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