PDF(Pubmed)
Abstract：
T cell engaging bispecific antibodies have shown clinical proof of concept for hematologic malignancies. Still, cytokine release syndrome, neurotoxicity, and on-target-off-tumor toxicity, especially in the solid tumor setting, represent major obstacles. Second generation TCEs have been described that decouple cytotoxicity from cytokine release by reducing the apparent binding affinity for CD3 and/or the TAA but the results of such engineering have generally led only to reduced maximum induction of cytokine release and often at the expense of maximum cytotoxicity. Using ROR1 as our model TAA and highly modular camelid nanobodies, we describe the engineering of a next generation decoupled TCE that incorporates a \"cytokine window\" defined as a dose range in which maximal killing is reached but cytokine release may be modulated from very low for safety to nearly that induced by first generation TCEs. This latter attribute supports pro-inflammatory anti-tumor activity including bystander killing and can potentially be used by clinicians to safely titrate patient dose to that which mediates maximum efficacy that is postulated as greater than that possible using standard second generation approaches. We used a combined method of optimizing TCE mediated synaptic distance and apparent affinity tuning of the TAA binding arms to generate a relatively long but persistent synapse that supports a wide cytokine window, potent killing and a reduced propensity towards immune exhaustion. Importantly, this next generation TCE induced significant tumor growth inhibition in vivo but unlike a first-generation non-decoupled benchmark TCE that induced lethal CRS, no signs of adverse events were observed.
摘要：
T细胞接合双特异性抗体已显示出血液恶性肿瘤概念的临床证据。尽管如此，细胞因子释放综合征，神经毒性，和上靶-外肿瘤毒性，尤其是在实体瘤环境中，是主要障碍。已经描述了第二代TCE,其通过降低对CD3和/或TAA的表观结合亲和力来使细胞毒性与细胞因子释放解耦,但是这种工程化的结果通常仅导致细胞因子释放的最大诱导减少,并且通常以最大细胞毒性为代价。使用ROR1作为我们的模型TAA和高度模块化的骆驼纳米体，我们描述了下一代解偶联TCE的工程改造,该TCE结合了一个\"细胞因子窗口\",定义为达到最大杀伤作用的剂量范围,但细胞因子释放可以从非常低的安全性调节到接近第一代TCE诱导的剂量范围.后一种属性支持包括旁观者杀伤在内的促炎抗肿瘤活性,并且可以被临床医生潜在地用于将患者剂量安全地滴定至认为比使用标准第二代方法可能更大的介导最大功效的剂量。我们使用了优化TCE介导的突触距离和TAA结合臂的表观亲和力调节的组合方法，以产生支持宽细胞因子窗口的相对较长但持久的突触。有效的杀伤和减少免疫衰竭的倾向。重要的是,这种下一代TCE在体内诱导了显着的肿瘤生长抑制，但与诱导致死性CRS的第一代非解偶联基准TCE不同，未观察到不良事件的迹象.
