2. Academic Validation
  3. Engineered bispecific antibodies targeting the interleukin-6 and -8 receptors potently inhibit cancer cell migration and tumor metastasis

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

  • Mol Ther. 2022 Jul 16;S1525-0016(22)00429-4. 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
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • 5 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.
  • 6 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.
  • 7 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.
  • 8 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. Electronic address: [email protected].
PMID: 35841152 DOI: 10.1016/j.ymthe.2022.07.008
Abstract

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.

Keywords

antibody; breast cancer; cell migration; interleukins; metastasis.

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