Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea.
Priority Research Center for Molecular Science &Technology, Ajou University, Suwon 16499, Republic of Korea.
Nat Commun. 2017 May 10;8:15090. doi: 10.1038/ncomms15090.
Oncogenic Ras mutants, frequently detected in human cancers, are high-priority anticancer drug targets. However, direct inhibition of oncogenic Ras mutants with small molecules has been extremely challenging. Here we report the development of a human IgG1 format antibody, RT11, which internalizes into the cytosol of living cells and selectively binds to the activated GTP-bound form of various oncogenic Ras mutants to block the interactions with effector proteins, thereby suppressing downstream signalling and exerting anti-proliferative effects in a variety of tumour cells harbouring oncogenic Ras mutants. When systemically administered, an RT11 variant with an additional tumour-associated integrin binding moiety for tumour tissue targeting significantly inhibits the in vivo growth of oncogenic Ras-mutated tumour xenografts in mice, but not wild-type Ras-harbouring tumours. Our results demonstrate the feasibility of developing therapeutic antibodies for direct targeting of cytosolic proteins that are inaccessible using current antibody technology.
致癌性 Ras 突变体在人类癌症中经常被检测到，是抗癌药物的首要靶点。然而，用小分子直接抑制致癌性 Ras 突变体极具挑战性。在这里，我们报告了一种人源 IgG1 格式抗体 RT11 的开发，它可以内化到活细胞的细胞质中，并选择性地与各种致癌性 Ras 突变体的激活 GTP 结合形式结合，从而阻断与效应蛋白的相互作用，从而抑制下游信号传导，并在携带致癌性 Ras 突变体的各种肿瘤细胞中发挥抗增殖作用。当系统给药时，具有额外肿瘤相关整联蛋白结合结构域以靶向肿瘤组织的 RT11 变体显著抑制了携带致癌性 Ras 突变的肿瘤异种移植物在小鼠体内的生长，但对携带野生型 Ras 的肿瘤没有抑制作用。我们的研究结果证明了开发用于直接靶向当前抗体技术无法接触的细胞质蛋白的治疗性抗体的可行性。
