Development of antibody drugs against novel targets and pathways offers great opportunities to improve current cancer treatment. We here describe a phenotypic discovery platform enabling efficient identification of therapeutic antibody-target combinations. The platform utilizes primary patient cells throughout the discovery process and includes methods for differential phage display cell panning, high-throughput cell-based specificity screening, phenotypic in vitro screening, target deconvolution, and confirmatory in vivo screening. In this study the platform was applied on cancer cells from patients with Chronic Lymphocytic Leukemia resulting in discovery of antibodies with improved cytotoxicity in vitro compared to the standard of care, the CD20-specific monoclonal antibody rituximab. Isolated antibodies were found to target six different receptors on Chronic Lymphocytic Leukemia cells; CD21, CD23, CD32, CD72, CD200, and HLA-DR of which CD32, CD200, and HLA-DR appeared as the most potent targets for antibody-based cytotoxicity treatment. Enhanced antibody efficacy was confirmed in vivo using a patient-derived xenograft model.

针对新型靶标和途径的抗体药物的开发为改善当前的癌症治疗提供了巨大的机会。我们在这里描述了能够有效鉴定治疗性抗体-靶标组合的表型发现平台。该平台在整个发现过程中利用了主要的患者细胞，并包括用于差异噬菌体展示细胞淘选，基于高通量细胞的特异性筛选，表型体外筛选，靶标解卷积和体内验证性筛选的方法。在这项研究中，该平台应用于患有慢性淋巴细胞性白血病患者的癌细胞，从而发现了与照护标准CD20特异性单克隆抗体利妥昔单抗相比在体外具有改善的细胞毒性的抗体。发现分离的抗体靶向慢性淋巴细胞白血病细胞上的六个不同受体。CD21，CD23，CD32，CD72，CD200和HLA-DR，其中CD32，CD200和HLA-DR似乎是基于抗体的细胞毒性治疗的最有效靶标。使用患者来源的异种移植模型在体内证实了增强的抗体功效。