A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models

Nicole Salazar, Jeffrey C. Carlson, Kexin Huang, Yayue Zheng, Cecilia Oderup, Julia Gross, Andrew D. Jang, Thomas M. Burke, Susanna Lewén, Alexander Scholz, Serina Huang, Leona Nease, Jon Kosek, Michel Mittelbronn, Eugene C. Butcher, Hua Tu, Brian A. Zabel*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Abstract

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM. Salazar et al. used hydrodynamic gene transfer to express a chimeric single chain antibody targeting the chemokine receptor CXCR7 in vivo. Antibody-mediated targeting of CXCR7 both alone and in combination with temozolomide enhanced the activation of innate immune cells to reduce tumor burden in mouse models of glioblastoma.

Original languageEnglish
Pages (from-to)1354-1365
Number of pages12
JournalMolecular Therapy
Volume26
Issue number5
DOIs
Publication statusPublished - 2 May 2018

Keywords

  • ADCP
  • DCC
  • MRI
  • TCGA
  • anti-tumor immune response
  • chemokine receptor
  • chimeric antibody
  • glioblastoma
  • hydrodynamic gene transfer

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