The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.

中文翻译：

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嵌合BET降解剂的抗体偶联可实现体内活性。

用双功能小分子选择性降解蛋白质的能力有可能从根本上改变各种疾病的治疗方法。然而，这些嵌合分子的相对大的尺寸通常导致具有挑战性的理化性质（例如，低的水溶性）和不良的药代动力学，这可能使它们的体内应用复杂化。我们最近发现了一种非常有效的嵌合BET降解物（GNE-987），该降解物表现出皮摩尔细胞的功效，但同时也显示出较低的体内暴露量。为了改善该分子的药代动力学特性，我们发现了第一个降解抗体-抗体共轭物，方法是通过新型接头将GNE-987与抗CLL1抗体连接。单次IV剂量的结合物可提供持续的体内暴露，从而导致抗原特异性肿瘤消退。