비스-벤즈이미다졸 STING 효능제 면역접합체 및 이의 용도

• Main Authors: SAFINA BRIAN, BRANDT GARY, KUDIRKA ROMAS, ZHOU MATTHEW
• Format: Patent
• Language: Korean
• Published: 29.02.2024
• Subjects: HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES

본 발명은 하나 이상의 STING 효능제 모이어티에 접합에 의해 연결된 항체를 포함하는 화학식 I의 면역접합체를 제공한다. 본 발명은 또한 반응성 작용기를 포함하는 STING 효능제-링커 중간 화합물을 제공한다. 이러한 중간체 조성물은 링커 또는 연결 모이어티를 통한 면역접합체의 형성을 위한 적합한 기질이다. 본 발명은 면역접합체로 암을 치료하는 방법을 추가로 제공한다. 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.