Targeted Anchoring Ecto-enzyme on Cancer Cell Surface to Enhance Antibody Therapy in Breast Cancer

摘要： 尽管抗HER2抗体曲妥珠单抗一直是HER2乳腺癌(BC)的主要治疗药物，但其临床益处在HER2患者中仍是异质性的，转移性HER2乳腺癌通常仍无法治愈。HER2抗体治疗的最终成功依赖于抗癌免疫的诱导，但这受到肿瘤微环境(TME)免疫抑制机制的限制，导致治疗耐药、转移，最终导致致死性BC。腺苷水平升高被认为是TME的主要免疫抑制机制，通过抑制抗体诱导的先天和获得性抗肿瘤免疫而导致对曲妥珠单抗的耐药性。腺苷脱氨酶(ADA)催化腺苷脱氨，并能逆转腺苷的免疫抑制活性。然而，全身性ADA给药在正常组织中会产生毒性，腺苷保护宿主免受过度免疫激活。我们假设，靶向锚定在HER2 BC细胞表面的ADA重新编程了TME中的免疫代谢，增强了HER2定向免疫治疗的有效性和安全性。我们已经开发出一种高度癌症特异性的靶向方法，将ADA运送到HER2 BC细胞的表面。以抗HER2抗体为靶向的ADA载体可使ADA定位于HER2 BC细胞表面，且表面锚定的ADA具有耗竭腺苷的能力。在荷瘤的同基因小鼠中，HER2靶向注射导致肿瘤ADA水平比自由注射ADA增加5.6倍。靶向的ADA传递导致TME重新编程进入免疫刺激的场景，并导致免疫介导的肿瘤消退。在拟议的研究中，我们将阐明表面ADA锚定(目标1)重新编程TME的机制，并将开发一种结合酪氨酸激酶抑制剂(目标2)增强表面ADA锚定的方法。该项目可以直接转化为治疗HER2 BC患者的靶向癌症免疫疗法。通过解决缺乏疾病特异性的问题，这是开发下一代免疫治疗方案的主要障碍，我们将为使用精确医学进行癌症免疫治疗做出贡献。

Abstract: Although the anti-HER2 antibody, trastuzumab, has been the mainstay of therapy for HER2+ breast cancer (BC), its clinical benefit remains heterogeneous among HER2+ patients and metastatic HER2+ BC remains generally incurable. The final success of HER2 antibody therapy relies on the induction of anticancer immunity, but this is limited by immunosuppressive mechanisms posed by the tumor microenvironment (TME), resulting in treatment resistance, metastasis, and ultimately lethal BC. Elevated adenosine level is considered a major immunosuppressive mechanism in the TME, causing resistance to trastuzumab by suppressing innate and adaptive antitumor immunity induced by the antibody. Adenosine deaminase (ADA) catalyzes the deamination of adenosine and is capable of reversing immunosuppressive activities of adenosine. However, systemic ADA administration causes toxicity in normal tissues, where adenosine protects the host from excessive immune activation. We hypothesize that targeted anchoring of ADA on HER2+ BC cell surface reprograms immunometabolism in the TME, enhancing the efficacy and safety of HER2-directed immunotherapy. We have developed a highly cancer specific targeting approach to deliver ADA to the surface of HER2+ BC cells. Targeted ADA delivery with an anti-HER2 antibody led to localization of ADA on the cell surface of HER2+ BC cells, and the surface-anchored ADA was capable of depleting adenosine. In tumor-bearing syngeneic mice, HER2-targeted delivery resulted in 5.6-fold increase in tumoral ADA level compared to free ADA administration. Targeted ADA delivery led to TME reprograming into an immunostimulatory landscape and resulted in immune-mediated tumor regression. In the proposed studies, we will elucidate the mechanisms of TME reprograming by surface ADA anchoring (Aim 1) and will develop an approach to enhance surface ADA anchoring by combination with a tyrosine kinase inhibitor (Aim 2). This project can be directly translated into a targeted cancer immunotherapy to treat patients with HER2+ BC. By addressing lack of disease specificity, a main obstacle to the development of next-generation immunotherapeutic regimens, we will contribute to the use of precision medicine for cancer immunotherapy.