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

Huilin Yang; Michelle N Karl; Wentao Wang; Bartholomew Starich; Haotian Tan; Ashley Kiemen; Alexandra B Pucsek; Yun-Huai Kuo; Gabriella C Russo; Tim Pan; Elizabeth M Jaffee; Elana J Fertig; Denis Wirtz; Jamie B Spangler

doi:10.1016/j.ymthe.2022.07.008

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

Mol Ther. 2022 Nov 2;30(11):3430-3449. doi: 10.1016/j.ymthe.2022.07.008. Epub 2022 Jul 16.

Authors

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: jamie.spangler@jhu.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Bispecific* / pharmacology
Antibodies, Bispecific* / therapeutic use
Antibodies, Monoclonal
Cell Movement
Humans
Interleukin-6 / genetics
Triple Negative Breast Neoplasms* / drug therapy

Substances

Antibodies, Bispecific
Interleukin-6
Antibodies, Monoclonal

Abstract

Publication types

MeSH terms

Substances

Grants and funding