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
  • 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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