Department of Immunotherapeutics and Biotechnology, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1718 Pine Street, Office 1306, Abilene, TX, 79601, USA.
BMC Biol. 2024 Mar 14;22(1):66. doi: 10.1186/s12915-024-01860-x.
Antibody drug conjugates (ADCs) constitute a promising class of targeted anti-tumor therapeutics that harness the selectivity of monoclonal antibodies with the potency of cytotoxic drugs. ADC development is best suited to initially screening antibody candidates for desired properties that potentiate target cell cytotoxicity. However, validating and producing an optimally designed ADC requires expertise and resources not readily available to certain laboratories.
In this study, we propose a novel approach to help streamline the identification of potential ADC candidates by utilizing a granzyme B (GrB)-based antibody fusion protein (AFP) for preliminary screening. GrB is a non-immunogenic serine protease expressed by immune effector cells such as CD8 + T cells that induces apoptotic activity and can be leveraged for targeted cell killing.
Our innovative model allows critical antibody parameters (including target cell binding, internalization, and cytotoxic potential) to be more reliably evaluated in vitro through the creation of an ADC surrogate. Successful incorporation of this AFP could also significantly expand and enhance ADC development pre-clinically, ultimately leading to the accelerated translation of ADC therapies for patients.
抗体药物偶联物（ADCs）是一类很有前途的靶向抗肿瘤治疗药物，它利用单克隆抗体的选择性和细胞毒性药物的效力。ADC 的开发最适合于最初筛选具有增强靶细胞细胞毒性的所需特性的抗体候选物。然而，验证和生产最佳设计的 ADC 需要专业知识和资源，某些实验室不容易获得。
在这项研究中，我们提出了一种新的方法，通过利用颗粒酶 B（GrB）为基础的抗体融合蛋白（AFP）进行初步筛选，帮助简化潜在 ADC 候选物的鉴定。GrB 是一种免疫原性丝氨酸蛋白酶，由免疫效应细胞（如 CD8+T 细胞）表达，可诱导细胞凋亡，并可用于靶向细胞杀伤。
我们的创新模型允许通过创建 ADC 替代物，更可靠地在体外评估关键的抗体参数（包括靶细胞结合、内化和细胞毒性潜力）。成功地将这种 AFP 整合进来，也可以显著地扩大和增强 ADC 的临床前开发，最终加速 ADC 治疗方法在患者中的应用。
