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INTRODUCTION: Immune-stimulating antibody conjugates (ISACs) consist of tumor-targeting antibodies conjugated to immune stimulants and are designed to activate the innate and adaptive immune systems against tumor cells following systemic administration. PD-L1 is an immune checkpoint that regulates anti-tumor T cell responses and is expressed on tumor cells as well as tumor-infiltrating immune cells across many tumor types. Here we show that PD-L1-targeted TLR7/8 ISACs elicit robust myeloid cell activation and can act through PD-L1 on either tumor or immune cells to improve anti-tumor responses compared to anti-PD-L1 treatment in preclinical tumor models. METHODS: A panel of proprietary anti-PD-L1 ISACs was evaluated for target-dependent in vitro myeloid cell activation by co-culturing PD-L1 expressing tumor cells with cDC-enriched primary myeloid cells. Anti-tumor efficacy of anti-PD-L1 ISACs was evaluated in vivo in both syngeneic and xenograft tumor models. MB49-PD-L1 KO cells were generated by knocking-out PD-L1 gene using CRISPR/Cas9 system. RESULTS: Anti-PD-L1 antibodies induced robust ADCP by myeloid effector cells and PD-L1/PD-1 blockade in vitro and in vivo. The conjugated PD-L1 ISACs induced robust, target-dependent activation of myeloid cells when co-cultured with tumor cells expressing PD-L1 at physiological levels, as measured by increased secretion of such cytokines as IL-12p70, TNFα, and IFNγ. Systemically administered surrogate PD-L1 ISACs were well tolerated in mice and showed improved anti-tumor efficacy over anti-PD-L1 antibodies, with significant tumor growth delay or complete responses frequently observed in syngeneic (e.g., MB49, MC38-hPD-L1) as well as xenograft (e.g., HCC1954-hPD-L1) tumor models. The improved in vivo efficacy of PD-L1 ISACs was sustained even in the absence of PD-L1 expression on tumor cells in syngeneic MB49-PD-L1 KO model suggesting that PD-L1 ISAC can induce its mechanism of action also through PD-L1 on myeloid cells. No tumor growth was observed after rechallenging mice previously cured with PD-L1 ISACs indicating development of immunological memory following the ISAC treatment. CONCLUSIONS: These preclinical data demonstrate the potential of a PD-L1-targeted ISAC as a novel multifunctional therapeutic that may improve efficacy of PD-L1/PD-1 inhibition by combining three mechanisms of action into a single molecule: TLR-mediated myeloid cell activation, T cell activation through immune-checkpoint inhibition as well as ADCP. Citation Format: Justin A. Kenkel, Rishali Gadkari, Po Y. Ho, Lisa K. Blum, Romas Kudirka, Karla A. Henning, William G. Mallet, Jennifer E. Melrose, Ganapathy Sarma, Steven J. Chapin, Matthew Zhou, Suprit Deol, Cindy Kreder, Yuyi Shen, Bruce Hug, Puneet Anand, Arthur Lee, Hai Li, Shelley E. Ackerman, Brian S. Safina, David Dornan, Michael N. Alonso, Marcin Kowanetz. PD-L1-targeted ISAC combines myeloid cell activation, immune-checkpoint inhibition and ADCP to improve anti-tumor efficacy over anti-PD-L1 antibodies in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4252. |
