Mechanisms of Cancer and Aging Laboratory, Department of Molecular and Cell Biology, University of Leicester, University Road, Leicester, LE1 7RH, UK.
Department of Biochemistry, Faculty of Physical Sciences, Cross River University of Technology, Calabar, Nigeria.
Sci Rep. 2021 Oct 13;11(1):20358. doi: 10.1038/s41598-021-99852-2.
A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer's and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody-drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.
大量研究表明，衰老细胞的积累会影响多种疾病，从纤维化到糖尿病、癌症、阿尔茨海默病和其他与年龄相关的病变。与此一致的是，清除衰老细胞可以延长体内模型的健康寿命和寿命。这为开发一类新的药物提供了依据，这类药物被称为衰老细胞清除剂，旨在选择性地清除人类组织中的衰老细胞。迄今为止，测试过的衰老细胞清除剂缺乏特异性，并且具有明显的脱靶效应，这表明靶向方法可能更具临床相关性。在这里，我们提议使用 B2M 的细胞外表位，即最近确定的衰老的膜标记物，作为将毒性药物特异性递送至衰老细胞的靶标。我们表明，针对 B2M 的抗体药物偶联物 (ADC) 通过向衰老细胞中释放 duocarmycin 来清除衰老细胞，而同种型对照 ADC 对这些细胞没有毒性。这种效应依赖于 p53 表达，因此在应激诱导的衰老中更为明显。非衰老细胞不受任何一种抗体的影响，证实了这种治疗的特异性。我们的结果提供了一个原理证明，即使用针对其表面蛋白组的第二代靶向衰老细胞清除剂来特异性清除衰老细胞的新方法，这可能在病理性衰老和相关疾病的临床应用中有价值。
