MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM
MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM
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DOI：
10.1073/pnas.1819085116
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发表时间：
2019-04-09
影响因子：
11.1
通讯作者：
MacBeath, Gavin
中科院分区：
文献类型：
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作者：
Casaletto, Jessica B.;Geddie, Melissa L.;MacBeath, Gavin
Met 受体酪氨酸激酶的激活，无论是通过其配体肝细胞生长因子 (HGF) 激活，还是通过配体独立机制（例如 MET 扩增或受体过度表达）激活，都与驱动肿瘤增殖、转移和治疗耐药有关。然而，Met 靶向抗体的临床开发一直具有挑战性，因为二价抗体表现出激动特性，而单价抗体缺乏效力和下调 Met 的能力。通过计算模型，我们发现通过引入识别肿瘤细胞表面上不相关的高表达抗原的第二个结合位点，可以显着提高靶向 Met 的单价抗体的效力。在这一预测的指导下，我们设计了 MM-131，这是一种对 Met 和上皮细胞粘附分子 (EpCAM) 都是单价的双特异性抗体。 MM-131 是一种纯拮抗性抗体，通过抑制 HGF 与 Met 结合并诱导受体下调，阻断配体依赖性和配体非依赖性 Met 信号传导。这些机制共同导致抑制 Met 驱动的癌细胞增殖、抑制 HGF 介导的癌细胞迁移以及抑制 HGF 依赖性和非依赖性小鼠异种移植模型中的肿瘤生长。与其设计一致，MM-131 在 EpCAM 高细胞中比在 EpCAM 低细胞中更有效，并且当 RNAi 降低 EpCAM 水平时，其效力会降低。对人类肿瘤样本中 Met、EpCAM 和 HGF 水平的评估表明，EpCAM 在多种 Met 阳性肿瘤类型中高水平表达，这表明 MM-131 的临床开发具有广阔的机会。
Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification or receptor overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development of Met-targeted antibodies has been challenging, however, as bivalent antibodies exhibit agonistic properties, whereas monovalent antibodies lack potency and the capacity to down-regulate Met. Through computational modeling, we found that the potency of a monovalent antibody targeting Met could be dramatically improved by introducing a second binding site that recognizes an unrelated, highly expressed antigen on the tumor cell surface. Guided by this prediction, we engineered MM-131, a bispecific antibody that is monovalent for both Met and epithelial cell adhesion molecule (EpCAM). MM-131 is a purely antagonistic antibody that blocks ligand-dependent and ligand-independent Met signaling by inhibiting HGF binding to Met and inducing receptor down-regulation. Together, these mechanisms lead to inhibition of proliferation in Met-driven cancer cells, inhibition of HGF-mediated cancer cell migration, and inhibition of tumor growth in HGF-dependent and -independent mouse xenograft models. Consistent with its design, MM-131 is more potent in EpCAM-high cells than in EpCAM-low cells, and its potency decreases when EpCAM levels are reduced by RNAi. Evaluation of Met, EpCAM, and HGF levels in human tumor samples reveals that EpCAM is expressed at high levels in a wide range of Met-positive tumor types, suggesting a broad opportunity for clinical development of MM-131.