Engineered bispecific antibodies targeting the interleukin-6 and -8 receptors potently inhibit cancer cell migration and tumor metastasis,Molecular Therapy

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Engineered bispecific antibodies targeting the interleukin-6 and -8 receptors potently inhibit cancer cell migration and tumor metastasis
Molecular Therapy ( IF 12.1 ) Pub Date : 2022-07-16 , DOI: 10.1016/j.ymthe.2022.07.008
Huilin Yang ₁ , Michelle N Karl ₂ , Wentao Wang ₃ , Bartholomew Starich ₂ , Haotian Tan ₂ , Ashley Kiemen ₂ , Alexandra B Pucsek ₄ , Yun-Huai Kuo ₁ , Gabriella C Russo ₂ , Tim Pan ₂ , Elizabeth M Jaffee ₅ , Elana J Fertig ₆ , Denis Wirtz ₇ , Jamie B Spangler ₈

Affiliation

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.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA; Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD 21218, USA; Convergence Institute, Johns Hopkins University, 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; Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Sidney Kimmel Cancer Center, the Johns Hopkins University, Baltimore, MD 21231, USA; Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA.

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.

中文翻译：

针对白介素 6 和 -8 受体的工程化双特异性抗体可有效抑制癌细胞迁移和肿瘤转移

同时抑制白细胞介素 6 (IL-6) 和白细胞介素 8 (IL-8) 信号传导可减少癌细胞迁移，最近显示联合治疗可协同减少三阴性乳腺癌临床前模型中的转移负担。在这里，我们设计了两种新型双特异性抗体，它们靶向 IL-6 和 IL-8 受体，同时阻断两种配体的信号传导活性。我们证明，一流的双特异性抗体设计具有广阔的治疗潜力，在转移性三阴性乳腺癌的细胞和动物模型中，与单克隆抗体和小分子药物组合相比，其选择性和效力增强。机制表征表明，我们的工程双特异性抗体对细胞活力没有影响，但大大降低了癌细胞的迁移潜力；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护理抗增殖药物相结合，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以转移为中心的创新方向。

更新日期：2022-07-16

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