Discovery Division, Merrimack Pharmaceuticals, Inc., Cambridge, MA 02139.
Discovery Division, Merrimack Pharmaceuticals, Inc., Cambridge, MA 02139;
Proc Natl Acad Sci U S A. 2019 Apr 9;116(15):7533-7542. doi: 10.1073/pnas.1819085116. Epub 2019 Mar 21.
Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as 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.
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)，还是通过配体非依赖性机制，如扩增或受体过表达，都与驱动肿瘤增殖、转移和对治疗的耐药性有关。然而，Met 靶向抗体的临床开发具有挑战性，因为二价抗体表现出激动剂特性，而单价抗体缺乏效力和下调 Met 的能力。通过计算建模，我们发现通过引入第二个结合位点来识别肿瘤细胞表面上无关的高度表达抗原，可以显著提高针对 Met 的单价抗体的效力。受此预测的指导，我们设计了 MM-131，这是一种针对 Met 和上皮细胞黏附分子 (EpCAM) 的双特异性抗体。MM-131 是一种纯拮抗抗体，通过抑制 HGF 与 Met 的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 Met 驱动的癌细胞增殖受到抑制、HGF 介导的癌细胞迁移受到抑制以及 HGF 依赖性和非依赖性小鼠异种移植模型中的肿瘤生长受到抑制。与设计一致，MM-131 在 EpCAM 高细胞中的效力比在 EpCAM 低细胞中的效力更高，并且当 EpCAM 水平通过 RNAi 降低时，其效力降低。对人类肿瘤样本中 Met、EpCAM 和 HGF 水平的评估表明，EpCAM 在广泛的 Met 阳性肿瘤类型中高表达，这表明 MM-131 具有广泛的临床开发机会。
