Faitschuk E, Nagy V, Hombach A A, Abken H
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Department I Internal Medicine, University Hospital Cologne, Cologne, Germany.
Gene Ther. 2016 Oct;23(10):718-726. doi: 10.1038/gt.2016.48. Epub 2016 Jun 14.
Adoptive cell therapy with chimeric antigen receptor (CAR)-modified T cells showed remarkable therapeutic efficacy in the treatment of leukaemia/lymphoma. However, the application to a variety of cancer entities is often constricted by the non-availability of a single chain antibody (scFv), which is usually the targeting domain in a CAR, while antibodies in the natural format are often available. To overcome the limitation, we designed a CAR that uses an antibody in its natural configuration for binding. Such CAR consists of two chains, the immunoglobulin light and heavy chain with their constant regions, whereby the heavy chain is anchored to the membrane and linked to an intracellular signalling domain for T-cell activation. The two chains form a stable heterodimer, a so-called dual chain CAR (dcCAR), and bind with high affinity and in a specific manner to their cognate antigen. By specific binding, the dcCAR activates engineered T cells for the release of pro-inflammatory cytokines and for target cell lysis. We provide evidence by three examples that the dcCAR format is universally applicable and thereby broadens the CAR cell therapy towards a larger variety of targets for which an scFv antibody is not available.
嵌合抗原受体（CAR）修饰的T细胞过继性细胞疗法在白血病/淋巴瘤治疗中显示出显著的治疗效果。然而，由于通常作为CAR靶向结构域的单链抗体（scFv）难以获得，而天然形式的抗体往往是可用的，因此该疗法在多种癌症实体中的应用常常受到限制。为克服这一限制，我们设计了一种使用天然构象抗体进行结合的CAR。这种CAR由两条链组成，即具有恒定区的免疫球蛋白轻链和重链，其中重链锚定在膜上并与用于T细胞激活的细胞内信号结构域相连。这两条链形成一个稳定的异二聚体，即所谓的双链CAR（dcCAR），并以高亲和力和特异性方式与其同源抗原结合。通过特异性结合，dcCAR激活工程化T细胞以释放促炎细胞因子并裂解靶细胞。我们通过三个例子证明了dcCAR形式具有普遍适用性，从而将CAR细胞疗法扩展到更广泛的、无法获得scFv抗体的靶点。
