Lu Zeyu, Truex Nicholas L, Melo Mariane B, Cheng Yiran, Li Na, Irvine Darrell J, Pentelute Bradley L
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, United States.
ACS Cent Sci. 2021 Feb 24;7(2):365-378. doi: 10.1021/acscentsci.0c01670. Epub 2021 Feb 4.
Therapeutic immunotoxins composed of antibodies and bacterial toxins provide potent activity against malignant cells, but joining them with a defined covalent bond while maintaining the desired function is challenging. Here, we develop novel immunotoxins by dovetailing full-length immunoglobulin G (IgG) antibodies and nontoxic anthrax proteins, in which the C terminus of the IgG heavy chain is connected to the side chain of anthrax toxin protective antigen. This strategy enabled efficient conjugation of protective antigen variants to trastuzumab (Tmab) and cetuximab (Cmab) antibodies. The conjugates effectively perform intracellular delivery of edema factor and N terminus of lethal factor (LF) fused with diphtheria toxin and Ras/Rap1-specific endopeptidase. Each conjugate shows high specificity for cells expressing human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR), respectively, and potent activity across six Tmab- and Cmab-resistant cell lines. The conjugates also exhibit increased pharmacokinetics and pronounced in vivo safety, which shows promise for further therapeutic development.
由抗体和细菌毒素组成的治疗性免疫毒素对恶性细胞具有强大的活性，但要以确定的共价键连接它们并同时保持所需功能具有挑战性。在此，我们通过将全长免疫球蛋白G（IgG）抗体与无毒炭疽蛋白相契合来开发新型免疫毒素，其中IgG重链的C末端连接到炭疽毒素保护性抗原的侧链。该策略实现了保护性抗原变体与曲妥珠单抗（Tmab）和西妥昔单抗（Cmab）抗体的有效偶联。这些偶联物有效地将与白喉毒素和Ras/Rap1特异性内肽酶融合的水肿因子和致死因子（LF）的N末端进行细胞内递送。每种偶联物分别对表达人表皮生长因子受体2（HER2）和表皮生长因子受体（EGFR）的细胞具有高度特异性，并对六种Tmab和Cmab耐药细胞系具有强大活性。这些偶联物还表现出增强的药代动力学和显著的体内安全性，这为进一步的治疗开发带来了希望。
