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Switchable immune modulator for tumor-specific activation of anticancer immunity.

ABSTRACT: Immune stimulatory antibodies and cytokines elicit potent antitumor immunity. However, the dose-limiting systemic toxicity greatly hinders their clinical applications. Here, we demonstrate a chemical approach, termed “switchable” immune modulator (Sw-IM), to limit the systemic exposure and therefore ameliorate their toxicities. Sw-IM is a biomacromolecular therapeutic reversibly masked by biocompatible polymers through chemical linkers that are responsive to tumor-specific stimuli, such as high reducing potential and acidic pH. Sw-IMs stay inert (switch off) in the circulation and healthy tissues but get reactivated (switch on) selectively in tumor via responsive removal of the polymer masks, thus focusing the immune boosting activities in the tumor microenvironment. Sw-IMs applied to anti–4-1BB agonistic antibody and IL-15 cytokine led to equivalent antitumor efficacy to the parental IMs with markedly reduced toxicities. Sw-IM provides a highly modular and generic approach to improve the therapeutic window and clinical applicability of potent IMs in mono- and combinational immunotherapies.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC8442900 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Switchable immune modulator for tumor-specific activation of anticancer immunity.

Zhao Yu Y Xie Yu-Qing YQ Van Herck Simon S Nassiri Sina S Gao Min M Guo Yugang Y Tang Li L

Science advances 20210910 37

Immune stimulatory antibodies and cytokines elicit potent antitumor immunity. However, the dose-limiting systemic toxicity greatly hinders their clinical applications. Here, we demonstrate a chemical approach, termed “switchable” immune modulator (Sw-IM), to limit the systemic exposure and therefore ameliorate their toxicities. Sw-IM is a biomacromolecular therapeutic reversibly masked by biocompatible polymers through chemical linkers that are responsive to tumor-specific stimuli, such as high ...[more]

PMID: 34516776

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Project description:In contrast to immune checkpoint inhibitors, the use of antibodies as agonists of immune costimulatory receptors as cancer therapeutics has largely failed. We sought to address this problem using a new class of modular synthetic drugs, termed tumor-targeted immune cell agonists (TICAs), based on constrained bicyclic peptides (Bicycles). Phage libraries displaying Bicycles were panned for binders against tumor necrosis factor (TNF) superfamily receptors CD137 and OX40, and tumor antigens EphA2, Nectin-4 and programmed death ligand 1. The CD137 and OX40 Bicycles were chemically conjugated to tumor antigen Bicycles with different linkers and stoichiometric ratios of binders to obtain a library of low molecular weight TICAs (MW <8 kDa). The TICAs were evaluated in a suite of in vitro and in vivo assays to characterize their pharmacology and mechanism of action. Linking Bicycles against costimulatory receptors (e.g., CD137) to Bicycles against tumor antigens (e.g., EphA2) created potent agonists that activated the receptors selectively in the presence of tumor cells expressing these antigens. An EphA2/CD137 TICA (BCY12491) efficiently costimulated human peripheral blood mononuclear cells in vitro in the presence of EphA2 expressing tumor cell lines as measured by the increased secretion of interferon γ and interleukin-2. Treatment of C57/Bl6 mice transgenic for the human CD137 extracellular domain (huCD137) bearing EphA2-expressing MC38 tumors with BCY12491 resulted in the infiltration of CD8+ T cells, elimination of tumors and generation of immunological memory. BCY12491 was cleared quickly from the circulation (plasma t1/2 in mice of 1-2 hr), yet intermittent dosing proved effective. Tumor target-dependent CD137 agonism using a novel chemical approach (TICAs) afforded elimination of tumors with only intermittent dosing suggesting potential for a wide therapeutic index in humans. This work unlocks a new path to effective cancer immunotherapy via agonism of TNF superfamily receptors.

Dataset Information

Switchable immune modulator for tumor-specific activation of anticancer immunity.

Publications

Switchable immune modulator for tumor-specific activation of anticancer immunity.

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