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    BIS-BENZIMIDAZOLE STING AGONIST IMMUNOCONJUGATES, AND USES THEREOF
    3.
    发明公开
    BIS-BENZIMIDAZOLE STING AGONIST IMMUNOCONJUGATES, AND USES THEREOF 审中-公开

    公开(公告)号：US20240335557A1

    公开(公告)日：2024-10-10

    申请号：US18573094

    申请日：2022-06-24

    申请人： BOLT BIOTHERAPEUTICS, INC.

    发明人： Gary BRANDT ,  Romas KUDIRKA ,  Brian SAFINA ,  Matthew ZHOU

    IPC分类号： A61K47/68 ,  A61K47/60

    CPC分类号： A61K47/6853 ,  A61K47/60 ,  A61K47/6803 ,  A61K47/6851 ,  A61K47/6889

    摘要： STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. While in principle systemic administration of a STING agonist would have many therapeutic benefits, including the delivery of STING to all tumor lesions, such an approach may be limited by toxicity. Antibody-drug conjugates (ADCs) constitute a proven therapeutic modality that is ideally suited to enable systemic administration without associated toxicity concerns via a targeted delivery strategy. Herein, we demonstrate that systemically administered STING agonist ADCs have greater anti-tumor activity as well as greatly improved tolerability compared to an intravenously (IV) administered, unconjugated (free) agonist. We generated novel STING agonist ADCs by leveraging our Immunosynthen platform, in which the chemical scaffold for bioconjugation is optimized for the STING agonist, resulting in an ADC that has desirable physicochemical and drug-like properties. We have studied the in vitro activity and mechanism of action of STING agonist ADCs in monoculture and co-culture systems. STING agonist ADCs were at least 100-fold more potent in inducing interferon and cytokines as well as tumor cell-killing relative to free agonist. STING agonist ADCs against several targets (antigens) have been evaluated for anti-tumor activity and pharmacodynamic and pharmacokinetic properties in multiple xenograft and syngeneic models. A single administration of STING agonist ADC resulted in target-dependent, durable, and complete regressions. Importantly, the STING agonist ADC led to an increase in tumor-localized inflammatory cytokines and significant immune cell infiltration, while levels of systemic cytokines remained low. In contrast, IV administered free agonist induced up to 100-fold higher levels of systemic cytokines with concomitant body weight loss but only modest tumor growth delay. In summary, Immunosynthen represents a novel STING agonist ADC platform. We have demonstrated target-dependent anti-tumor immune responses in vitro and in vivo for multiple targets, tumor models, and mouse strains. In each case the STING agonist ADC was more active and better tolerated than the IV administered free agonist.