Zappala Fabiana, Higbee-Dempsey Elizabeth, Jang Bian, Miller Joann, Yan Lesan, Minutolo Nicholas G, Rosado González Gabriela T, Tsourkas Andrew, Ozdemir Burcin Altun
Department of Bioengineering, University of Pennsylvania, 210 S. 33rd Street, 240 Skirkanich Hall, Philadelphia, PA 19104, USA.
Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.
Sci Adv. 2022 May 6;8(18):eabn4613. doi: 10.1126/sciadv.abn4613.
Extensive antibody engineering and cloning is typically required to generate new bispecific antibodies. Made-to-order genes, advanced expression systems, and high-efficiency cloning can simplify and accelerate this process, but it still can take months before a functional product is realized. We developed a simple method to site-specifically and covalently attach a T cell-redirecting domain to any off-the-shelf, human immunoglobulin G (IgG) or native IgG isolated from serum. No antibody engineering, cloning, or knowledge of the antibody sequence is required. Bispecific antibodies are generated in just hours. By labeling antibodies isolated from tumor-bearing mice, including two syngeneic models, we generated T cell-redirecting autoantibodies (TRAAbs) that act as an effective therapeutic. TRAAbs preferentially bind tumor tissue over healthy tissue, indicating a previously unexplored therapeutic window. The use of autoantibodies to direct the tumor targeting of bispecific antibodies represents a new paradigm in personalized medicine that eliminates the need to identify tumor biomarkers.
通常需要进行广泛的抗体工程和克隆来生成新的双特异性抗体。定制基因、先进的表达系统和高效克隆可以简化并加速这一过程，但在获得功能性产品之前仍可能需要数月时间。我们开发了一种简单的方法，可将T细胞重定向结构域位点特异性地共价连接到任何现成的、从血清中分离出的人免疫球蛋白G（IgG）或天然IgG上。无需进行抗体工程、克隆或了解抗体序列。双特异性抗体只需数小时即可生成。通过标记从荷瘤小鼠（包括两种同基因模型）中分离出的抗体，我们生成了可作为有效治疗剂的T细胞重定向自身抗体（TRAAbs）。TRAAbs优先结合肿瘤组织而非健康组织，这表明存在一个此前未被探索的治疗窗口。利用自身抗体来指导双特异性抗体的肿瘤靶向作用代表了个性化医学中的一种新范式，无需识别肿瘤生物标志物。
