Validation and humanization of a PET imaging agent that targets PD-L1.

针对 PD-L1 的 PET 显像剂的验证和人源化。

• 批准号: 9138543
• 负责人: Monica Gostissa
• 金额: $ 30万
• 依托单位: AGENUS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-22 至 2018-03-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9138543
• 关键词: Achievement; Affinity; Amino Acid Sequence; Antibodies; Antigens; Biodistribution; Biological Markers; Biopsy; Blocking Antibodies; Blood; Buffers; CD8B1 gene; Cell Line; Cell surface; Cells; Clinical; Cytotoxic T-Lymphocytes; Data; Detection; Development; Discipline of Nuclear Medicine; Dose; Drug Kinetics; Funding; Goals; Hour; Human; Image; Imagery; Imaging Techniques; Imaging technology; Immune; Immunohistochemistry; Immunologic Surveillance; Injection of therapeutic agent; Isotopes; Label; Lead; Lesion; Life; Llama; Location; Measurement; Measures; Melanoma Cell; Metastatic Melanoma; Modeling; Mus; Neoplasm Metastasis; Noise; PDCD1LG1 gene; Patient Selection; Patients; Penetration; Peptide Sequence Determination; Performance; Pharmacology and Toxicology; Phase; Physicians; Physiological; Positioning Attribute; Positron-Emission Tomography; Primary Neoplasm; Production; Protein Engineering; Proteins; Qualifying; Radiation; Radio; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Reagent; Recruitment Activity; Regimen; Renal clearance function; Resolution; Sampling Biases; Signal Transduction; Site; Site-Directed Mutagenesis; Small Business Innovation Research Grant; Specificity; Stratification; Surface; System; T-Lymphocyte; Technology; Testing; Tissues; Tumor Markers; Tumor-Infiltrating Lymphocytes; Validation; X-Ray Computed Tomography; Xenograft procedure; adaptive immunity; antibody inhibitor; base; bioimaging; cancer cell; cancer immunotherapy; cancer therapy; clinical efficacy; cost; design; exhaust; experience; exposed human population; imaging agent; immunodeficient mouse model; immunogenicity; inhibitor/antagonist; lymph nodes; melanoma; mouse model; neoplastic cell; non-invasive imaging; potential biomarker; pre-clinical; predicting response; predictive marker; public health relevance; radiotracer; research study; response; sortase; standard of care; tumor; tumor immunology; tumor xenograft; uptake; whole body imaging

 DESCRIPTION (provided by applicant): Several strategies have recently shown convincing clinical efficacy by stimulating adaptive immunity for the treatment of cancer. 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 shown significant efficacy in metastatic melanoma, and are in testing for the treatment of numerous other tumor types, either alone or in combination. Expression of the cell surface marker PD-L1, either on TILS at the tumor margin or on the tumor itself, appears to be correlated with clinical efficacy in CpI therapy, identifying it as a potential biomarker for patiet stratification and management. The current standard for assessment of this biomarker entails biopsy of primary and metastatic tumor foci, followed by immunohistochemical characterization. Limitations of biopsy include low patient and physician acceptance due to its invasiveness and 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. We are developing a positron emission tomography (PET) agent that can non-invasively image PD-L1. Our product uses site-specific conjugation for controlled and reproducible installation of a radio-isotopic label on single domain antibodies (sdAbs). Due to its small size, the resulting imaging agents show high tissue uptake and rapid renal clearance. This design allows an exceptionally high PET signal to noise ratio, even at low levels of antigen abundance and within 2 hours of injection, enabling same day imaging at high resolution. Our mouse proof of concept experiments using radiolabelled sdAbs to specific immune cell and tumor markers shows exceptionally high resolution imaging of lymph nodes and tumors. 121 Bio has assembled a highly qualified scientific team with broad experience in protein engineering, antibody discovery and development, tumor immunology and nuclear medicine. To supplement internal capabilities, we have gained access to additional outside facilities and have recruited a panel of expert tumor immunology and PET imaging consultants. We propose here to prepare PD-L1-reactive sdAbs radiolabeled with either 89Zr or 18F. The resulting imaging data will guide our selection of the optimal radiolabel for development of our radiodiagnostic product. We will also formally demonstrate that human tumors can be visualized using our lead candidate antibody against PD-L1. Finally, we will humanize the sdAb in order to reduce potential immunogenicity. This anti-PD-L1 imaging agent offers the potential to be the first non-invasive imaging agent to be used in selection and management of patients undergoing cancer immunotherapy.

 描述（由申请人提供）：最近，几种策略通过刺激适应性免疫治疗癌症显示出令人信服的临床疗效。例如，免疫检查点抑制剂（CpIs）通过阻断导致肿瘤浸润淋巴细胞（TIL）耗尽的相互作用来重新激活患者自身的T细胞以消除肿瘤。CpIs在转移性黑色素瘤中显示出显著的疗效，并且正在测试单独或组合治疗许多其他肿瘤类型。细胞表面标志物PD-L1的表达，无论是在肿瘤边缘的TILS上还是在肿瘤本身上，似乎与CpI治疗的临床疗效相关，将其确定为患者分层和管理的潜在生物标志物。目前评估该生物标志物的标准需要对原发性和转移性肿瘤病灶进行活检，然后进行免疫组化表征。活检的局限性包括由于其侵入性和难以在许多解剖位置进入肿瘤而导致的患者和医生接受度低，以及与肿瘤病灶内和肿瘤病灶之间的标记物异质分布相关的采样偏倚，增加了假阴性结果的可能性。迫切需要非侵入性成像技术，其允许在不同解剖位置处的原发性和转移性肿瘤病灶的整个表面上的生物标志物分布的可视化。121 Bio在开发这种非侵入性成像方法方面具有独特的优势。我们正在开发一种可以非侵入性成像PD-L1的正电子发射断层扫描（PET）试剂。我们的产品使用位点特异性缀合，用于在单域抗体（sdAb）上受控和可再现地安装放射性同位素标记。由于其尺寸小，所得的显像剂显示出高组织摄取和快速肾清除。这种设计允许极高的PET信噪比，即使在低水平的抗原丰度和注射后2小时内，也能在同一天以高分辨率成像。我们使用放射性标记的sdAb对特异性免疫细胞和肿瘤标志物进行的小鼠概念验证实验显示出淋巴结和肿瘤的异常高分辨率成像。121 Bio组建了一支高素质的科学团队，在蛋白质工程、抗体发现和开发、肿瘤免疫学和核医学方面拥有丰富的经验。为了补充内部能力，我们已经获得了额外的外部设施，并聘请了一个专家肿瘤免疫学和PET成像顾问小组。我们在此提出制备用89 Zr或18F放射性标记的PD-L1反应性sdAb。由此产生的成像数据将指导我们选择最佳的放射性标记，用于开发我们的放射诊断产品。我们还将正式证明人类肿瘤可以使用我们针对PD-L1的主要候选抗体进行可视化。最后，我们将sdAb人源化以降低潜在的免疫原性。这种抗PD-L1显像剂有可能成为第一种用于选择和管理接受癌症免疫治疗的患者的非侵入性显像剂。