In recent years, HER3 has increasingly been implicated in the progression of a variety of tumor types and in acquired resistance to EGFR and HER2 therapies. Whereas EGFR and HER2 primarily signal through the MAPK pathway, HER3, as a heterodimer with EGFR or HER2, potently activates the PI3K pathway. Despite its critical role, previous attempts to target HER3 with neutralizing antibodies have shown disappointing efficacy in the clinic, most likely due to suboptimal and indirect mechanisms of action that fail to completely block heterodimerization; for example, tumors can escape inhibition of ligand binding by upregulating ligand-independent mechanisms of HER3 activation. We therefore developed 10D1F, a picomolar affinity, highly specific anti-HER3 neutralizing antibody that binds the HER3 heterodimerization interface, a region that was hitherto challenging to raise antibodies against. We demonstrate that 10D1F potently inhibits both EGFR:HER3 and HER2:HER3 heterodimerization to durably suppress activation of the PI3K pathway in a broad panel of tumor models. Even as a monotherapy, 10D1F shows superior inhibition of tumor growth in the same cell lines both in vitro and in mouse xenograft experiments, when compared with other classes of anti-HER3 antibodies. This includes models demonstrating ligand-independent activation of heterodimerization as well as constitutively activating mutations in the MAPK pathway. Possessing favorable pharmacokinetic and toxicologic profiles, 10D1F uniquely represents a new class of anti-HER3 neutralizing antibodies with a novel mechanism of action that offers significant potential for broad clinical benefit. 10D1F is a novel anti-HER3 antibody that uniquely binds the receptor dimerization interface to block ligand-dependent and independent heterodimerization with EGFR/HER2 and thus more potently inhibits tumor growth than existing anti-HER3 antibodies.

中文翻译：

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10D1F 是一种抗 HER3 抗体，可独特地阻断受体异二聚化界面，有效抑制广泛的肿瘤模型中的肿瘤生长

近年来，HER3 越来越多地与多种肿瘤类型的进展以及对 EGFR 和 HER2 疗法的获得性耐药有关。EGFR 和 HER2 主要通过 MAPK 途径发出信号，而 HER3 作为与 EGFR 或 HER2 的异二聚体，有效地激活 PI3K 途径。尽管其作用至关重要，但以前用中和抗体靶向 HER3 的尝试在临床上表现出令人失望的疗效，很可能是由于未能完全阻断异二聚化的次优和间接作用机制；例如，肿瘤可以通过上调 HER3 激活的配体非依赖性机制来逃避配体结合的抑制。因此，我们开发了 10D1F，一种皮摩尔亲和力、高度特异性的抗 HER3 中和抗体，可结合 HER3 异二聚化界面，一个迄今为止难以产生抗体的地区。我们证明 10D1F 可有效抑制 EGFR:HER3 和 HER2:HER3 异二聚化，从而在广泛的肿瘤模型中持久抑制 PI3K 通路的激活。即使作为单一疗法，与其他类别的抗 HER3 抗体相比，10D1F 在体外和小鼠异种移植实验中也显示出对相同细胞系肿瘤生长的卓越抑制。这包括证明异源二聚化的配体独立激活以及 MAPK 途径中的组成型激活突变的模型。10D1F 具有良好的药代动力学和毒理学特征，独特地代表了一类具有新作用机制的新型抗 HER3 中和抗体，为广泛的临床益处提供了巨大的潜力。