Development of immuno-PET agents for the selective imaging of CD8 T cells

项目摘要 寻求刺激适应性免疫以治疗癌症的治疗策略最近已被发现。 显示出令人信服的临床疗效。例如，免疫检查点抑制剂（CPI）可以重新激活患者自身的 T细胞通过阻断导致肿瘤浸润淋巴细胞（TILs）成为 耗尽. CPI已经证明了对转移性黑色素瘤和非小细胞肺癌的显着成功。 肺癌，并正在测试治疗许多其他类型的肿瘤，无论是单独或组合。 CD8+细胞毒性T细胞对肿瘤的浸润似乎是CPI治疗有效的必要条件。 因此，CD8已被鉴定为对CPI疗法的响应的潜在预测生物标志物，至少 黑色素瘤目前评估这种生物标志物的标准需要对原发性和转移性肿瘤进行活检。 肿瘤病灶，然后进行免疫组织化学表征。活检的局限性包括其侵入性， 在许多解剖位置进入肿瘤的困难，以及与肿瘤相关的采样偏差， 标记物在肿瘤病灶内和肿瘤病灶之间的不均匀分布，增加了假阳性的可能性。 负面结果。目前迫切需要非侵入性成像技术， 不同解剖结构下原发性和转移性肿瘤病灶整个表面上的生物标志物分布 地点121 Bio在开发这种非侵入性成像方法方面具有独特的优势。我们的平台 利用单域抗体（sdAb）的优势，结合位点特异性缀合， 用于正电子发射断层扫描（PET）的放射性同位素标记的受控和可再现的安装 显像由于它们的小尺寸，所得到的成像剂显示出高组织摄取和快速血液流动。 间隙这种设计允许高PET肿瘤与背景比率，即使在低水平的抗原丰度下也是如此 并且在注射后2至4小时内，能够在同一天以高分辨率成像。鼠标概念验证 使用针对特异性免疫标记物的放射性标记的sdAb的实验已经成功地可视化了 免疫细胞内的淋巴结构和肿瘤的PET成像。121Bio已经组建了一个高素质的 科学团队在蛋白质工程、抗体发现和开发、肿瘤 免疫学和核医学。为了补充内部能力，我们还获得了外部渠道， 我们已经招募了一个肿瘤免疫学和PET成像专家小组。我们有 产生了一系列小鼠和人CD8反应性sdAb，并在此提出：a）进一步表征 它们在小鼠模型中检测肿瘤浸润性CD8 T细胞的能力，和B）选择和表征先导物 用于人类的候选人。这种抗CD8显像剂提供了成为 第一种用于选择和管理CPI癌症患者的非侵入性成像剂 免疫疗法

Project summary Therapeutic strategies that seek to stimulate adaptive immunity for the treatment of cancer have recently shown convincing clinical efficacy. Immune checkpoint inhibitors (CPIs), for example, reactivate a patient’s own T cells to eliminate tumors by blocking interactions that cause tumor infiltrating lymphocytes (TILs) to become exhausted. CPIs have demonstrated remarkable success against metastatic melanoma and non-small cell lung cancer, and are in testing for the treatment of numerous other tumor types, either alone or in combination. Infiltration of the tumor by CD8+ cytotoxic T cells appears to be a requisite for CPI treatment to be effective. Accordingly, CD8 has been identified as a potential predictive biomarker for response to CPI therapy, at least in melanoma. The current standard for assessment of this biomarker entails biopsy of primary and metastatic tumor foci, followed by immunohistochemical characterization. Limitations of biopsy include its invasiveness, the difficulty of accessing tumors at many anatomical locations, and sampling bias related to the heterogeneous distribution of markers both within and between tumor foci, increasing the likelihood of false negative results. There is an urgent need for non-invasive imaging techniques that allow visualization of biomarker distribution on the entire surface of primary and metastatic tumor foci at diverse anatomical locations. 121 Bio is uniquely positioned to develop such a non-invasive imaging approach. Our platform exploits the advantages of single domain antibodies (sdAbs), combined with site-specific conjugation for controlled and reproducible installation of a radio-isotopic label for positron emission tomography (PET) imaging. Due to their small size, the resulting imaging agents show high tissue uptake and rapid blood clearance. This design allows high PET tumor-to-background ratios, even at low levels of antigen abundance and within 2 to 4 hours of injection, enabling same day imaging at high resolution. Mouse proof of concept experiments using radiolabelled sdAbs against specific immune markers have were successful at visualizing immune cells within lymphoid structure and tumors by PET imaging. 121Bio has assembled a highly qualified scientific team with broad experience in protein engineering, antibody discovery and development, tumor immunology and nuclear medicine. To complement internal capabilities, we have gained access to outside facilities and have recruited a panel of expert tumor immunology and PET imaging consultants. We have generated a series of mouse and human CD8-reactive sdAbs, and propose here to: a) further characterize their ability to detect tumor-infiltrating CD8 T cells in mouse models, and b) select and characterize the lead candidate for development toward use in humans. This anti-CD8 imaging agent offers the potential to be the first non-invasive imaging agent to be used in selection and management of patients underdoing CPI cancer immunotherapy.