肿瘤细胞治疗研究
英文原题：Broad reactivity and enhanced potency of recombinant anti-EGFR × anti-CD3 bispecific antibody-armed activated T cells against solid tumours.
引言：双特异性抗体（BiAb）武装的活化T细胞（BATs）构成了一种用于治疗癌症的过继性T细胞治疗平台。
引言：双特异性抗体（BiAb）武装的活化T细胞（BATs）构成了一种用于治疗癌症的过继性T细胞治疗平台。用抗CD3 x 抗肿瘤相关抗原（TAA）BiAbs武装活化T细胞（ATC），可将ATC转化为非主要组织相容性复合体（MHC）限制性的抗肿瘤细胞毒性T淋巴细胞（CTLs）。通过BiAb桥接靶抗原的结合，可实现特异性抗肿瘤细胞毒性、Th1细胞因子释放和T细胞增殖。使用化学异源偶联BiAbs武装的BATs在乳腺癌、前列腺癌和胰腺癌中进行的临床试验证明了安全性、可行性、抗肿瘤免疫反应的诱导以及总生存期（OS）的潜在提高。目的：本研究的主要目的是开发一种重组BiAb，赋予BATs针对广泛实体瘤的增强抗肿瘤活性。方法：设计了一种重组抗表皮生长因子受体（EGFR）x 抗CD3（OKT3）BiAb（rEGFRBi），并在CHO细胞中表达，用于武装ATC（rEGFR-BATs），并测试其针对乳腺癌、胰腺癌、前列腺癌和胶质母细胞瘤的特异性细胞毒性。结果：与各自对应的化学异源偶联BATs相比，rEGFR-BATs对广泛实体瘤细胞系表现出显著增强的特异性细胞毒性和T1细胞因子分泌。结论：rEGFR-BATs可能提供一种用于治疗广泛实体瘤的“通用”T细胞疗法。关键信息：将scFv的可变轻链和重链之间融合至重链抗体N端的（Gly4Ser）6连接肽，赋予重链融合蛋白意想不到的稳定性，并支持双特异性抗体的高效表达。用rEGFRBi武装活化T细胞可显著增强T细胞相对于化学异源偶联BiAbs的相对细胞毒性和Th1细胞因子分泌。rEGFR-BATs是治疗广泛实体瘤的有前景候选药物。
Introduction: Bispecific antibody (BiAb)-armed activated T cells (BATs) comprise an adoptive T cell therapy platform for treating cancer. Arming activated T cells (ATC) with anti-CD3 x anti-tumour associated antigen (TAA) BiAbs converts ATC into non-major histocompatibility complex (MHC)-restricted anti-tumour cytotoxic T lymphocytes (CTLs). Binding of target antigens via the BiAb bridge enables specific anti-tumour cytotoxicity, Th1 cytokines release, and T cell proliferation. Clinical trials in breast, prostate, and pancreatic cancer using BATs armed with chemically heteroconjugated BiAbs demonstrated safety, feasibility, induction of anti-tumour immune responses and potential increases in overall survival (OS). Objectives: The primary objective of this study was to develop a recombinant BiAb that confers enhanced anti-tumour activity of BATs against a broad range of solid tumours. Methods: A recombinant anti-epidermal growth factor receptor (EGFR) x anti-CD3 (OKT3) BiAb (rEGFRBi) was designed and expressed in CHO cells, used to arm ATC (rEGFR-BATs), and tested for specific cytotoxicity against breast, pancreatic and prostate cancers and glioblastoma. Results: rEGFR-BATs exhibit remarkably enhanced specific cytotoxicity and T1 cytokine secretion against a wide range of solid tumour cell lines vs. their respective chemically-heteroconjugated BATs. Conclusion: rEGFR-BATs may provide a "universal" T cell therapy for treating a wide range of solid tumours. KEY MESSAGEA (Gly4Ser)6 linker between the variable light and heavy chains of an scFv fused to the N-terminus of a heavy chain antibody confers unexpected stability to the heavy chain fusion protein and supports the efficient expression of the bispecific antibody.Arming of activated T cells with the rEGFRBi greatly enhances the relative cytotoxicity and Th1 cytokine secretion of theT cells relative to a chemically heteroconjugated BiAbs.rEGFR-BATs are promising candidates for the treatment of a broad range of solid tumours.
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