Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for Nano Biotechnology (INBT), the Johns Hopkins University, Baltimore, MD 21218, USA.
Mol Ther. 2022 Nov 2;30(11):3430-3449. doi: 10.1016/j.ymthe.2022.07.008. Epub 2022 Jul 16.
Simultaneous inhibition of interleukin-6 (IL-6) and interleukin-8 (IL-8) signaling diminishes cancer cell migration, and combination therapy has recently been shown to synergistically reduce metastatic burden in a preclinical model of triple-negative breast cancer. Here, we have engineered two novel bispecific antibodies that target the IL-6 and IL-8 receptors to concurrently block the signaling activity of both ligands. We demonstrate that a first-in-class bispecific antibody design has promising therapeutic potential, with enhanced selectivity and potency compared with monoclonal antibody and small-molecule drug combinations in both cellular and animal models of metastatic triple-negative breast cancer. Mechanistic characterization revealed that our engineered bispecific antibodies have no impact on cell viability, but profoundly reduce the migratory potential of cancer cells; hence they constitute a true anti-metastatic treatment. Moreover, we demonstrate that our antibodies can be readily combined with standard-of-care anti-proliferative drugs to develop effective anti-cancer regimens. Collectively, our work establishes an innovative metastasis-focused direction for cancer drug development.
同时抑制白细胞介素-6（IL-6）和白细胞介素-8（IL-8）信号通路会降低癌细胞的迁移能力，最近的临床前研究表明，联合治疗可协同降低三阴性乳腺癌的转移负担。在这里，我们设计了两种新型的双特异性抗体，靶向 IL-6 和 IL-8 受体，同时阻断两种配体的信号活性。我们证明了一种首创的双特异性抗体设计具有很有前途的治疗潜力，与单克隆抗体和小分子药物组合在转移性三阴性乳腺癌的细胞和动物模型中具有增强的选择性和效力。机制特征表明，我们设计的双特异性抗体对细胞活力没有影响，但能显著降低癌细胞的迁移能力；因此，它们构成了真正的抗转移治疗。此外，我们证明我们的抗体可以很容易地与标准的抗增殖药物联合使用，以开发有效的抗癌方案。总的来说，我们的工作为癌症药物开发建立了一个创新的以转移为重点的方向。
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