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）治疗的主要药物，但其临床获益在HER2+患者中仍不均匀，转移性HER2+ BC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）造成的免疫抑制机制的限制，导致治疗耐药性、转移和最终致死的BC。腺苷水平升高被认为是TME中的主要免疫抑制机制，通过抑制抗体诱导的先天性和适应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）催化腺苷的脱氨作用，能够逆转腺苷的免疫抑制活性。然而，全身性ADA给药在正常组织中引起毒性，其中腺苷保护宿主免于过度免疫激活。我们假设ADA靶向锚定在HER 2 + BC细胞表面重新编程TME中的免疫代谢，从而增强HER 2靶向免疫治疗的疗效和安全性。我们开发了一种高度癌症特异性的靶向方法，将ADA递送至HER2+ BC细胞的表面。用抗HER2抗体靶向ADA递送导致ADA定位在HER2+ BC细胞的细胞表面上，并且表面锚定的ADA能够消耗腺苷。在荷瘤同基因小鼠中，与游离ADA给药相比，HER2靶向给药导致肿瘤ADA水平增加5.6倍。靶向ADA递送导致TME重编程为免疫刺激景观，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TME重编程的机制（目标1），并将开发一种方法，以增强表面ADA锚定结合酪氨酸激酶抑制剂（目标2）。该项目可以直接转化为靶向癌症免疫疗法，治疗HER2+ BC患者。通过解决缺乏疾病特异性，这是下一代免疫疗法开发的主要障碍，我们将为癌症免疫疗法的精准医学的使用做出贡献。

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.