A Dual Action Antibody Drug Conjugate to Treat Triple Negative Breast Cancer by Enhancing Tumor Immunity

项目摘要 三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的形式，占所有乳腺癌的15%。 乳腺癌，在50岁以下的妇女中广泛流行。尽管有新的治疗方法， TNBC患者很穷。最近，免疫肿瘤学（IO）疗法显示出改善肿瘤的潜力。 通过使患者的免疫系统能够对肿瘤发起攻击来改善治疗结果。当IO 药物改善了治疗结果，但它们的反应率尚未充分发挥潜力，因为它们无法 产生免疫原性肿瘤。IO药物仅从癌细胞中去除免疫抑制， 来自免疫抑制细胞的免疫抑制，从而保留免疫抑制肿瘤 微环境（TME），使免疫系统无法发动有效的攻击， 残留的肿瘤导致IO药物的功效降低。为了避免这个问题， 被认为产生免疫原性肿瘤（例如，单独或联合药物消除免疫抑制细胞 以消除癌细胞和免疫抑制细胞）。然而，目前可用的方法可能导致 由于TME外的免疫细胞的非特异性消除而引起的免疫毒性。因此，有必要 开发治疗策略，选择性地消除TME内的免疫抑制细胞，同时还 消除癌细胞以有效地产生免疫原性肿瘤，从而促进通过免疫系统去除肿瘤， 系统为了满足这一需求，TRIO制药公司（TRIO）正在开发一种专有的双重作用药物，肿瘤 免疫原性增强抗体偶联物™（TIEAC™），其通过肿瘤-免疫反应产生免疫原性肿瘤。 特异性消除癌细胞和免疫抑制细胞。对于第一阶段计划，TRIO是 开发用于TNBC的TIEAC™，称为TRIO-525。TRIO-525旨在改善治疗结果， 通过TNBC细胞的肿瘤特异性消除产生免疫原性肿瘤， 免疫抑制细胞这使得免疫效应细胞能够对肿瘤发起有效的攻击。我们 主要创新包括：1）通过在肿瘤中富集药物来消除TME驻留的免疫抑制细胞 富含抗原的肿瘤; 2）通过结合特异性受体的新设计选择性靶向免疫抑制细胞 以允许消除免疫抑制细胞而不消耗其他免疫细胞，从而降低免疫抑制细胞的免疫活性， 毒性初步数据显示，TRIO-525在临床前肿瘤模型中表现出单药活性， 用于消除TNBC细胞和免疫抑制细胞的选择性双重功能性。在此，整个第一阶段 目的是通过两个目的将TRIO-525确立为用于TNBC的有效新疗法： TRIO-525在体外消耗免疫抑制细胞和增强T细胞应答中的作用;和 在临床相关体内模型中的疗效研究。第一阶段的成功完成将为消除风险提供数据 TRIO-525作为一种有前途的治疗和去风险II期安全性和转化研究提案，以推进 IND的努力。

PROJECT SUMMARY Triple Negative Breast Cancer (TNBC) is the most aggressive form of breast cancer accounting for 15% of all breast cancers and is widely prevalent in women < 50 years old. Despite new treatments, the survivability of TNBC patients is poor. Recently, immuno-oncology (IO) therapies demonstrated the potential to improve treatment outcomes by enabling a patient’s immune system to launch an attack against the tumor. While IO drugs improved treatment outcome, their response rate has not reached full potential as they are unable to generate immunogenic tumors. IO drugs solely remove immunosuppression from cancer cells leaving immunosuppression from immunosuppressor cells intact, thus retaining an immunosuppressive tumor microenvironment (TME) whereby the immune system is unable to launch an effective attack against the remaining tumor resulting in reduced efficacy of IO drugs. To circumvent this problem, various strategies are considered to create immunogenic tumors (e.g., eliminating immunosuppressor cells alone or combining drugs to eliminate both cancer cells and immunosuppressor cells). However, currently available approaches can lead to immune toxicities due to non-specific elimination of immune cells outside of the TME. Thus, there is a need to develop treatment strategies to selectively eliminate immunosuppressor cells within the TME, whilst also eliminating cancer cells to effectively create an immunogenic tumor to facilitate tumor removal by the immune system. To address this need, TRIO Pharmaceuticals (TRIO) is developing a proprietary dual-action drug, Tumor Immunogenicity Enhancing Antibody Conjugate™ (TIEAC™), that generates immunogenic tumors by tumor- specific elimination of both cancer cells and immunosuppressor cells. For this Phase I program, TRIO is developing a TIEAC™ for TNBC, referred to as TRIO-525. TRIO-525 aims to improve treatment outcomes in TNBC patients by generating immunogenic tumors by tumor-specific elimination of TNBC cells and immunosuppressor cells. This enables immune effector cells to launch an effective attack against the tumor. Our key innovations include: 1) Eliminating TME-residing immunosuppressor cells by enriching the drug in the tumor antigen rich tumor; 2) Selective targeting of immunosuppressor cells by a novel design to bind a specific receptor to allow eliminating immunosuppressor cells without depleting other immune cells thereby lowering immune toxicity. Preliminary data shown TRIO-525 exhibits single-agent activity in preclinical cancer models with tumor- selective dual functionality for eliminating TNBC cells and immunosuppressor cells. Herein, the overall Phase I goal is to establish TRIO-525 as an effective novel therapy for TNBC accomplished by two aims: i) Selectivity of TRIO-525 in depleting immunosuppressor cells and augmenting T-cell responses in vitro; and ii) Therapeutic efficacy studies in clinically relevant models in vivo. Successful completion of Phase I will provide data to de-risk TRIO-525 as a promising therapy and de-risk Phase II proposal of safety and translation studies to advance the IND efforts.