A fully humanized IgG-like bispecific antibody for effective dual targeting of CXCR3 and CCR6

Remy Robert, Laurent Juglair, Ee X. Lim, Caroline Ang, Carl J.H. Wang, Gregor Ebert, Olan Dolezal, Charles R. Mackay

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic. We therefore hypothesized that simultaneous targeting of both CXCR3 and CCR6 with a bispecific antibody (BsAb) might result in decreased chemotaxis and/or specific depletion of pro-inflammatory T cell subsets. In this study, we designed and characterized a fully humanized BsAb. We show that the BsAb binds to both chemokine receptors, as demonstrated by Flow Cytometry and Surface Plasmon Resonance analysis. Furthermore, we demonstrate that the BsAb effectively blocks cell chemotaxis and induces specific antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Therefore, we propose that dual targeting of CXCR3 and CCR6 with a fully humanized BsAb may display a potent interventional approach for the treatment of inflammatory and autoimmune diseases.

Original languageEnglish
Article numbere0184278
Number of pages18
JournalPLoS ONE
Volume12
Issue number9
DOIs
Publication statusPublished - 5 Sep 2017

Keywords

  • flow cytometry
  • cell staining
  • lymphocytes
  • chemokines
  • cloning
  • antibodies
  • immune cells
  • inflammatory diseases

Cite this

Robert, Remy ; Juglair, Laurent ; Lim, Ee X. ; Ang, Caroline ; Wang, Carl J.H. ; Ebert, Gregor ; Dolezal, Olan ; Mackay, Charles R. / A fully humanized IgG-like bispecific antibody for effective dual targeting of CXCR3 and CCR6. In: PLoS ONE. 2017 ; Vol. 12, No. 9.
@article{2c584e24f95d4a228bf79cc2ae5784d7,
title = "A fully humanized IgG-like bispecific antibody for effective dual targeting of CXCR3 and CCR6",
abstract = "Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic. We therefore hypothesized that simultaneous targeting of both CXCR3 and CCR6 with a bispecific antibody (BsAb) might result in decreased chemotaxis and/or specific depletion of pro-inflammatory T cell subsets. In this study, we designed and characterized a fully humanized BsAb. We show that the BsAb binds to both chemokine receptors, as demonstrated by Flow Cytometry and Surface Plasmon Resonance analysis. Furthermore, we demonstrate that the BsAb effectively blocks cell chemotaxis and induces specific antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Therefore, we propose that dual targeting of CXCR3 and CCR6 with a fully humanized BsAb may display a potent interventional approach for the treatment of inflammatory and autoimmune diseases.",
keywords = "flow cytometry, cell staining, lymphocytes, chemokines, cloning, antibodies, immune cells, inflammatory diseases",
author = "Remy Robert and Laurent Juglair and Lim, {Ee X.} and Caroline Ang and Wang, {Carl J.H.} and Gregor Ebert and Olan Dolezal and Mackay, {Charles R.}",
year = "2017",
month = "9",
day = "5",
doi = "10.1371/journal.pone.0184278",
language = "English",
volume = "12",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

A fully humanized IgG-like bispecific antibody for effective dual targeting of CXCR3 and CCR6. / Robert, Remy; Juglair, Laurent; Lim, Ee X.; Ang, Caroline; Wang, Carl J.H.; Ebert, Gregor; Dolezal, Olan; Mackay, Charles R.

In: PLoS ONE, Vol. 12, No. 9, e0184278, 05.09.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A fully humanized IgG-like bispecific antibody for effective dual targeting of CXCR3 and CCR6

AU - Robert, Remy

AU - Juglair, Laurent

AU - Lim, Ee X.

AU - Ang, Caroline

AU - Wang, Carl J.H.

AU - Ebert, Gregor

AU - Dolezal, Olan

AU - Mackay, Charles R.

PY - 2017/9/5

Y1 - 2017/9/5

N2 - Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic. We therefore hypothesized that simultaneous targeting of both CXCR3 and CCR6 with a bispecific antibody (BsAb) might result in decreased chemotaxis and/or specific depletion of pro-inflammatory T cell subsets. In this study, we designed and characterized a fully humanized BsAb. We show that the BsAb binds to both chemokine receptors, as demonstrated by Flow Cytometry and Surface Plasmon Resonance analysis. Furthermore, we demonstrate that the BsAb effectively blocks cell chemotaxis and induces specific antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Therefore, we propose that dual targeting of CXCR3 and CCR6 with a fully humanized BsAb may display a potent interventional approach for the treatment of inflammatory and autoimmune diseases.

AB - Chemokines and their receptors are pivotal for the trafficking of leukocytes during immune responses, and host defense. However, immune cell migration also contributes to a wide variety of autoimmune and chronic inflammatory diseases. Compelling evidence suggests that both CXCR3 and CCR6 chemokine receptors play crucial roles in the migration of pathological Th1 and Th17 cells during the course of certain inflammatory diseases. The use of two or more receptors by pathogenic cells may explain why targeting of individual receptors has proven disappointing in the clinic. We therefore hypothesized that simultaneous targeting of both CXCR3 and CCR6 with a bispecific antibody (BsAb) might result in decreased chemotaxis and/or specific depletion of pro-inflammatory T cell subsets. In this study, we designed and characterized a fully humanized BsAb. We show that the BsAb binds to both chemokine receptors, as demonstrated by Flow Cytometry and Surface Plasmon Resonance analysis. Furthermore, we demonstrate that the BsAb effectively blocks cell chemotaxis and induces specific antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. Therefore, we propose that dual targeting of CXCR3 and CCR6 with a fully humanized BsAb may display a potent interventional approach for the treatment of inflammatory and autoimmune diseases.

KW - flow cytometry

KW - cell staining

KW - lymphocytes

KW - chemokines

KW - cloning

KW - antibodies

KW - immune cells

KW - inflammatory diseases

UR - http://www.scopus.com/inward/record.url?scp=85028936846&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0184278

DO - 10.1371/journal.pone.0184278

M3 - Article

VL - 12

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 9

M1 - e0184278

ER -