PO.ET08.02 · 实验与分子治疗
利用靶向肿瘤胞内抗原PRAME的可溶性T细胞受体TCR开发针对PRAME阳性肿瘤的治疗与放射性诊断制剂
Utilize a soluble T-cell receptor TCR targeting tumor intracellular antigen PRAME to develop therapeutic and radioactive diagnostic agents for PRAME-positive tumors
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摘要 Abstract
中文摘要
基于T细胞受体（TCR）的治疗与诊断在靶向由HLA分子呈递的胞内肿瘤抗原方面展现出巨大前景。黑色素瘤优先表达抗原（PRAME）在许多癌症中表达，但在正常组织中高度受限，使其成为基于TCR疗法的良好靶点。我们建立了一个专有的高效TCR发现平台，能够从健康供者和癌症患者中快速鉴定抗原特异性TCR。从健康供者中克隆出特异性靶向PRAME425-433肽/HLA-A*02:01复合物的TCR。用编码PRAME特异性TCR的慢病毒转导的T细胞以抗原特异性方式表现出强健的IFN-gamma分泌和溶细胞功能。通过对TCR α链和β链的恒定区进行工程改造，实现了单价和双价天然TCR的可溶性表达。我们开发了一种独有的基于细胞的TCR结合测定法，以筛选和鉴定具有不同亲和力的可溶性天然PRAME特异性TCR。表面等离子体共振（SPR）分析表明，双价天然TCR蛋白HP-002以KD为1.08 × 10⁻⁷ M结合PRAME425-433/HLA-A*02:01。该双价天然TCR被用于开发TCR-CD3 T细胞衔接器和用于成像的放射性诊断制剂。碘-125（125I）标记的双价天然TCR蛋白HP-002在异种移植肿瘤模型中通过SPECT/CT成像表现出体内抗原依赖性肿瘤蓄积。这些数据突显了我们的发现与分子工程平台开发用于癌症治疗和放射性诊断的可溶性TCR的能力。我们正在进行的工作聚焦于HP-002的TCR亲和力成熟和分子优化，以改善其亲和力和选择性，旨在实现增强的肿瘤蓄积，用于未来的诊断和治疗应用。
查看英文原文 English abstract
T-cell receptor (TCR)-based therapeutics and diagnostics hold great promise for targeting intracellular tumor antigens presented by HLA molecules. The preferentially expressed antigen in melanoma (PRAME) is expressed in many cancers, but is highly restricted in normal tissues, making it a good target for TCR-based therapy. We have established a proprietary high-efficiency TCR discovery platform, enabling rapid identification of antigen-specific TCRs from healthy donors and cancer patients. TCRs specifically targeting PRAME425-433 peptide/ HLA-A*02:01 complex were cloned from healthy donors. T cells transduced with lentivirus encoding PRAME-specific TCR exhibited robust IFN-gamma secretion and cytolytic function in an antigen-specific manner. By engineering the constant regions of both TCR alpha and beta chains, the soluble expression of monovalent and bivalent native TCRs was achieved. We developed an exclusive cell based TCR binding assay to screen and identify the soluble forms of native PRAME-specific TCRs with various affinities. Surface plasmon resonance (SPR) analysis demonstrated that the bivalent native TCR protein HP-002 binds PRAME425-433/HLA-A*02:01 with a KD of 1.08 × 10⁻⁷ M. The Bivalent native TCR was used to develop TCR-CD3 T cell engager and radioactive diagnostic agent for imaging. Iodine-125 (125I)-labeled bivalent native TCR protein HP-002 exhibited in vivo antigen-dependent tumor accumulation in xenograft tumor models by SPECT/CT imaging. These data highlight the capability of our discovery and molecular engineering platform to develop the soluble TCRs for therapeutics and radioactive diagnostics in cancer. Our ongoing work focuses on TCR affinity maturation and molecular optimization of HP-002 to improve its affinity and selectivity, aiming to achieve enhanced tumor accumulation for future diagnostic and therapeutic applications.
利益披露 Disclosure
Y. Huang, None.