https://blog.superhyydl.org/tags/tim3/Recent content in TIM3 on Superhyydl's BlogHugozh-cnSun, 06 Sep 2026 00:00:00 +0000https://blog.superhyydl.org/reading/tim3-targeted-delivery-of-venetoclax-overcomes-drug/Sun, 06 Sep 2026 00:00:00 +0000https://blog.superhyydl.org/reading/tim3-targeted-delivery-of-venetoclax-overcomes-drug/<h2 id="一句话亮点">一句话亮点</h2> <p>浙大黄河/钱鹏旭团队开发了一款名为VINCENT的双抗纳米平台，一头抓住AML细胞上的TIM3，一头拽住NK细胞上的CD16，同时精准投放维奈克拉。它既解决了耐药问题，又把“躺平”的NK细胞拉回战场，在耐药PDX模型中显著延长生存。</p> <h2 id="背景痛点">背景/痛点</h2> <p>维奈克拉（VEN）联合去甲基化药物是老年/unfit AML患者的基石方案，但原发耐药（~20-30%）和获得性耐药（&gt;40%缓解者复发）是临床硬骨头。TIM3是个有意思的靶点：它在白血病干细胞（LSC）上高表达，在正常造血干上不表达，且与VEN耐药正相关；同时它又是NK、T细胞上的抑制性受体。TIM3抗体（如sabatolimab）联合VEN的临床试验结果令人失望（NCT04150029）。那问题出在哪？</p> <p>@方法论点评：靶点选对了，但单抗只能“松开刹车”，无法“踩油门”——既不能定向增敏耐药细胞，也没解决瘤内NK细胞数量少、功能耗竭的问题。作者假设：把VEN精准送到TIM3+细胞上，同时通过CD16拉住NK细胞形成免疫突触，或许能实现“1+1&gt;2”。</p> <h2 id="推理链分步拆解">推理链分步拆解</h2> <h3 id="1-先搞定递送怎么把ven装到抗tim3抗体上">1. 先搞定递送：怎么把VEN装到抗TIM3抗体上？</h3> <p>作者用IR-783-NHS作为连接臂，利用NHS-酯-胺化学反应，将抗CD16和抗TIM3抗体共价偶联到VEN自组装的纳米颗粒上，得到VINCENT。粒径~226.6 nm，在血清中稳定72 h，药物释放呈pH依赖性（溶酶体酸性环境触发）。</p> <p>@方法论点评：用NHS化学偶联是成熟路线；关键在于他们用分子动力学模拟先验证了IR-783-NHS与VEN自组装能力没受影响，属于“计算指导实验”的策略，避免盲目试错。</p> <p>接着验证亲和力：VINCENT对CD16^hi NK细胞的Kd为0.31 nM，对TIM3+ AML细胞的Kd为0.27 nM，特异性很强。活细胞成像显示，VINCENT在20分钟内就能拉近NK细胞和AML细胞形成稳定的“免疫突触”。</p> <p><img alt="Fig. 1：Construction of VINCENT and the evaluation of targeted affinity and biodistribution in AML mice. a, Scheme of the generation of VEN NPs and loading of anti-CD16 and anti-TIM3 onto VEN NPs (VINCENT; left), along with the proposed mechanism for VINCENT (right). Scheme created in BioRender; Li, J. https://BioRender.com/5l29djy (2025). b, TEM images of VEN NPs and VINCENT. c, TEM images of immunogold analysis of VEN NPs and VINCENT using anti-IgG (H + L) antibody–gold bioconjugate. d, Mean fluorescence intensity analysis of IR-783 at NIR channel in NK cells or Molm-13 cells. e, Fluorescence visualization of VINCENT after 20-min incubation with CD16bri NK cells or TIM3+ Molm-13 cells (VINCENT, red; nuclei, blue; CD16 or TIM3, green). f, Fluorescence live imaging of VINCENT-mediated engagement between CD16bri NK cells and TIM3+ Molm-13 cells (VINCENT, red; CD16bri NK cells, blue; TIM3+ Molm-13 cells, green). g, Proportion of NK cells that do not bind to Molm-13 cells in the live imaging cocultures. Each point represents the mean proportion of nonbinding NK cells" loading="lazy" src="https://blog.superhyydl.org/images/reading/tim3-targeted-delivery-of-venetoclax-overcomes-drug/figure-01.png"></p>