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

双重作用抗体药物偶联物通过增强肿瘤免疫来治疗三阴性乳腺癌

• 批准号: 10480128
• 负责人: Reiner Laus
• 金额: $ 39.87万
• 依托单位: TRIO PHARMACEUTICALS INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480128
• 关键词: Accounting; Address; Affinity; Antibodies; Antibody-drug conjugates; Antigen Targeting; Antigens; Antineoplastic Agents; Binding; Blood Circulation; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; CD34 gene; CD8B1 gene; Cancer Etiology; Cancer Model; Cancer Patient; Cells; Cessation of life; Clinical; Clinical Trials; Coculture Techniques; Data; Effector Cell; Excision; Exhibits; Fatty acid glycerol esters; Goals; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immunooncology; Immunosuppression; Immunosuppressive Agents; In Vitro; Laboratories; Lead; Malignant Neoplasms; Measures; Mediating; Myeloid Cells; Myeloid-derived suppressor cells; New Drug Approvals; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prognosis; Resistance; Risk; Safety; Small Business Innovation Research Grant; T cell response; T-Cell Proliferation; T-Lymphocyte; Testing; Toxic effect; Toxin; Toxin Conjugates; Translations; Transplantation; Treatment Efficacy; Treatment outcome; Tumor Antigens; Tumor Burden; Tumor Immunity; Woman; Xenograft procedure; aggressive breast cancer; alpha Toxin; alternative treatment; anti-PD-1; antibody conjugate; arm; cancer cell; clinically relevant; cohort; design; drug action; effector T cell; efficacy evaluation; efficacy study; humanized mouse; immune clearance; immunogenic; immunogenicity; improved; in vivo; in vivo Model; innovation; malignant breast neoplasm; mammary; monocyte; mouse model; nonhuman primate; novel; novel therapeutics; overexpression; pre-clinical; prevent; programs; receptor; response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor-immune system interactions

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.

项目概要 三阴性乳腺癌 (TNBC) 是最具侵袭性的乳腺癌形式，占所有乳腺癌的 15% 乳腺癌，在 50 岁以下的女性中广泛流行。尽管有新的治疗方法，但患者的生存能力 TNBC 患者很穷。最近，免疫肿瘤学 (IO) 疗法证明了改善病情的潜力 通过使患者的免疫系统对肿瘤发起攻击来达到治疗效果。而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 药物仅消除癌细胞的免疫抑制 来自完整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），使免疫系统无法对病原体发起有效攻击 残留的肿瘤导致 IO 药物疗效降低。为了规避这个问题，有多种策略 被认为会产生免疫原性肿瘤（例如，单独消除免疫抑制细胞或联合药物 消除癌细胞和免疫抑制细胞）。然而，目前可用的方法可以导致 由于非特异性消除 TME 之外的免疫细胞而产生的免疫毒性。因此，有必要 制定治疗策略以选择性消除 TME 内的免疫抑制细胞，同时还 消除癌细胞，有效产生免疫原性肿瘤，促进免疫系统清除肿瘤 系统。为了满足这一需求，TRIO Pharmaceuticals (TRIO) 正在开发一种专有的双作用药物——Tumor 免疫原性增强抗体偶联物™ (TIEAC™)，通过肿瘤产生免疫原性肿瘤 特异性消除癌细胞和免疫抑制细胞。对于这个第一阶段计划，TRIO 是 开发用于 TNBC 的 TIEAC™，称为 TRIO-525。 TRIO-525 旨在改善以下疾病的治疗结果 TNBC 患者通过肿瘤特异性消除 TNBC 细胞产生免疫原性肿瘤， 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。我们的 主要创新包括：1）通过富集肿瘤中的药物来消除 TME 驻留的免疫抑制细胞 富含抗原的肿瘤； 2）通过新颖的设计选择性靶向免疫抑制细胞以结合特定受体 允许消除免疫抑制细胞而不耗尽其他免疫细胞，从而降低免疫 毒性。初步数据显示 TRIO-525 在临床前癌症模型中表现出单药活性 选择性消除 TNBC 细胞和免疫抑制细胞的双重功能。其中，第一期总体 目标是将 TRIO-525 确立为一种有效的 TNBC 新疗法，通过两个目标实现： i) TRIO-525 在体外消耗免疫抑制细胞并增强 T 细胞反应； ii) 治疗性 临床相关模型的体内功效研究。第一阶段的成功完成将为降低风险提供数据 TRIO-525 作为一种有前景的疗法，可降低安全性和转化研究的 II 期提案，以推进 IND 的努力。