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

Humans Animals Antibodies, Bispecific / pharmacology Interleukin-6 / genetics Triple Negative Breast Neoplasms / drug therapy Antibodies, Monoclonal Cell Movement
antibody breast cancer cell migration interleukins metastasis

Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
02 11 2022
Historique:
received: 12 02 2022
revised: 12 06 2022
accepted: 09 07 2022
pubmed: 17 7 2022
medline: 8 11 2022
entrez: 16 7 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ymthe.2022.07.008 PMID: 35841152 PMC: PMC9637575
pubmed: 35841152
pii: S1525-0016(22)00429-4
doi: 10.1016/j.ymthe.2022.07.008
pmc: PMC9637575
pii:
doi:

Substances chimiques

Antibodies, Bispecific 0
Interleukin-6 0
Antibodies, Monoclonal 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

3430-3449

Subventions

Organisme : NCI NIH HHS
ID : U54 CA210173
Pays : United States

Informations de copyright

Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors have filed intellectual property covering the technologies described herein. E.J.M., D.W., and J.B.S. are co-founders of AbMeta Therapeutics.

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Auteurs

Huilin Yang (H)

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.

Michelle N Karl (MN)

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.

Wentao Wang (W)

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.

Bartholomew Starich (B)

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.

Haotian Tan (H)

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.

Ashley Kiemen (A)

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.

Alexandra B Pucsek (AB)

Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Yun-Huai Kuo (YH)

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.

Gabriella C Russo (GC)

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.

Tim Pan (T)

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.

Elizabeth M Jaffee (EM)

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.

Elana J Fertig (EJ)

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.

Denis Wirtz (D)

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.

Jamie B Spangler (JB)

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.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Engineered bispecific antibodies targeting the...
questionsmedicales.fr › Eucaryotes › Animaux › Engineered bispecific antibodies targeting the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps bispécifiques › Engineered bispecific antibodies targeting the...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Interleukines › Interleukine-6 › Engineered bispecific antibodies targeting the...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Tumeurs du sein triple-négatives › Engineered bispecific antibodies targeting the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Anticorps monoclonaux › Engineered bispecific antibodies targeting the...
questionsmedicales.fr › Phénomènes physiologiques › Mouvement cellulaire › Engineered bispecific antibodies targeting the...