PO.ET02.04 · 实验与分子治疗
一种通过消除肿瘤微环境中的免疫抑制来治疗实体瘤的新型双特异性ADC
A novel bispecific ADC to treat solid tumors by removing immunosuppression in the tumor microenvironment
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摘要 Abstract
中文摘要
TNBC仍是侵袭性最强的乳腺癌之一，当前抗体和免疫肿瘤治疗方案收效有限，很大程度上是由于肿瘤微环境中髓源性抑制细胞（MDSC）的持续存在。我们开发了一种新型双作用双特异性抗体药物偶联物（ADC）——TRIO-525，一种同类首创的肿瘤免疫原性增强抗体偶联物（TIE-ADC），旨在实现对癌细胞（通过TROP2）和MDSC（通过CD33）的肿瘤选择性、双靶向清除。在机制上，TRIO-525采用一种独特的抗体构型，经工程化设计以对TROP2具有更高亲和力，并实现对CD33的肿瘤选择性结合，从而在肿瘤内选择性清除免疫抑制性MDSC，同时保留造血细胞和其他免疫细胞。临床前研究证实了TRIO-525受体介导的细胞毒性。它相较于现有疗法表现出更优的效力和特异性，能在纳摩尔浓度下有效且选择性地杀伤TNBC细胞和MDSC，恢复T细胞增殖，并完全保留健康免疫细胞。TRIO-525在异种移植模型中诱导强健的剂量依赖性肿瘤消退，无任何毒性或脱靶效应。TRIO-525还表现出卓越的血浆稳定性，无降解产物。这些发现确立了TRIO-525作为一种生成免疫原性肿瘤的突破性解决方案，直接克服了TME驱动的免疫抑制——这是TNBC和实体瘤治疗中的未满足需求。以TRIO-525为代表的TIE-ADC药物的开发，标志着癌症免疫治疗的范式转变，通过同时、肿瘤选择性地根除恶性细胞和免疫抑制细胞，在克服治疗耐药性和改善患者预后方面具有广泛意义。
查看英文原文 English abstract
TNBC remains one of the most aggressive breast cancers, with limited success from current antibody and immuno-oncology regimens, largely due to the persistence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We developed a novel dual-action bispecific antibody drug conjugate (ADC), TRIO-525, a first-in-class Tumor Immunogenicity Enhancing Antibody Conjugate (TIE-ADC) designed for tumor-selective, dual-targeted elimination of both cancer cells (via TROP2) and MDSCs (via CD33).Mechanistically, TRIO-525 utilizes a unique antibody format engineered for higher affinity to TROP2 and, tumor-selective engagement of CD33, enabling selective depletion of immunosuppressive MDSCs within the tumor while sparing hematopoietic and other immune cells. Preclinical studies confirmed TRIO-525's receptor-mediated cytotoxicity. It demonstrated superior potency and specificity compared to existing therapies, with effective and selective killing of both TNBC cells and MDSCs at nanomolar concentrations, restoration of T cell proliferation, and full preservation of healthy immune cells. TRIO-525 induces robust, dose-dependent tumor regression in xenograft models without any toxicity or off-target effects. TRIO-525 also displays exceptional plasma stability with no degradation species.These findings establish TRIO-525 as a ground-breaking solution to generate immunogenic tumors, directly overcoming TME-driven immunosuppression-an unmet need in TNBC and solid tumor therapy. The development of TIE-ADC drugs, as exemplified by TRIO-525, signals a paradigm shift in cancer immunotherapy through simultaneous, tumor-selective eradication of malignant and immunosuppressive cells, with broad implications for overcoming therapeutic resistance and improving patient outcomes.
利益披露 Disclosure
S. Bhowmik, None..
W. Brady, None.