W van der Wulp, W Luu, M E Ressing, J Schuurman, S I van Kasteren, L Guelen, R C Hoeben, B Bleijlevens, M H M Heemskerk
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引用次数: 0
Abstract
Antibody-mediated delivery of immunogenic viral CD8+ T-cell epitopes to redirect virus-specific T cells toward cancer cells is a promising new therapeutic avenue to increase the immunogenicity of tumors. Multiple strategies for viral epitope delivery have been shown to be effective. So far, most of these have relied on a free C-terminus of the immunogenic epitope for extracellular delivery. Here, we demonstrate that antibody-epitope conjugates (AECs) with genetically fused epitopes to the N-terminus of the antibody can also sensitize tumors for attack by virus-specific CD8+ T cells. AECs carrying epitopes genetically fused at the N-terminus of the light chains of cetuximab and trastuzumab demonstrate an even more efficient delivery of the T-cell epitopes compared to AECs with the epitope fused to the C-terminus of the heavy chain. We demonstrate that this increased efficiency is not caused by the shift in location of the cleavage site from the N- to the C-terminus, but by its increased proximity to the cell surface. We hypothesize that this facilitates more efficient epitope delivery. These findings not only provide additional insights into the mechanism of action of AECs but also broaden the possibilities for genetically fused AECs as an avenue for the redirection of multiple virus-specific T cells toward tumors.
抗体介导的免疫原性病毒 CD8+ T 细胞表位递送可将病毒特异性 T 细胞重新导向癌细胞,是一种很有希望的提高肿瘤免疫原性的新疗法。多种病毒表位递送策略已被证明是有效的。迄今为止,这些策略大多依赖于免疫原表位的游离 C 端进行细胞外递送。在这里,我们证明了将表位基因融合到抗体 N 端的抗体-表位共轭物(AECs)也能使肿瘤受到病毒特异性 CD8+ T 细胞的攻击。与将表位融合在重链 C 端的 AEC 相比,将表位基因融合在西妥昔单抗和曲妥珠单抗轻链 N 端的 AEC 能更有效地传递 T 细胞表位。我们证明,效率的提高并不是因为裂解位点从 N 端转移到了 C 端,而是因为裂解位点更接近细胞表面。我们假设这有利于更有效地传递表位。这些发现不仅让我们对 AECs 的作用机制有了更多的了解,而且拓宽了基因融合 AECs 作为将多种病毒特异性 T 细胞重新导向肿瘤的途径的可能性。
期刊介绍:
mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.