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

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.

SUBMITTER: Salazar N

PROVIDER: S-EPMC5993942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledThe atypical chemokine receptor ACKR3 (formerly CXCR7), overexpressed in various cancers compared with normal tissues, plays a pivotal role in adhesion, angiogenesis, tumorigenesis, metastasis, and tumor cell survival. ACKR3 modulates the tumor microenvironment and regulates tumor growth. The therapeutic potential of ACKR3 has also been demonstrated in various murine models of human cancer. Literature findings underscore the importance of ACKR3 in disease progression and suggest it as an important diagnostic marker for noninvasive imaging of ACKR3-overexpressing malignancies. There are currently no reports on direct receptor-specific detection of ACKR3 expression. Here we report the evaluation of a radiolabeled ACKR3-targeted monoclonal antibody (ACKR3-mAb) for the noninvasive in vivo nuclear imaging of ACKR3 expression in human breast, lung, and esophageal squamous cell carcinoma cancer xenografts.MethodsACKR3 expression data were extracted from Cancer Cell Line Encyclopedia, The Cancer Genome Atlas, and the Clinical Lung Cancer Genome Project. (89)Zr-ACKR3-mAb was evaluated in vitro and subsequently in vivo by PET and ex vivo biodistribution studies in mice xenografted with breast (MDA-MB-231-ACKR3 [231-ACKR3], MDA-MB-231 [231], MCF7), lung (HCC95), or esophageal (KYSE520) cancer cells. In addition, ACKR3-mAb was radiolabeled with (125)I and evaluated by SPECT imaging and ex vivo biodistribution studies.ResultsACKR3 transcript levels were highest in lung squamous cell carcinoma among the 21 cancer type data extracted from The Cancer Genome Atlas. Also, Clinical Lung Cancer Genome Project data showed that lung squamous cell carcinoma had the highest CXCR7 transcript levels compared with other lung cancer subtypes. The (89)Zr-ACKR3-mAb was produced in 80% ± 5% radiochemical yields with greater than 98% radiochemical purity. In vitro cell uptake of (89)Zr-ACKR3-mAb correlated with gradient levels of cell surface ACKR3 expression observed by flow cytometry. In vivo PET imaging and ex vivo biodistribution studies in mice with breast, lung, and esophageal cancer xenografts consistently showed enhanced (89)Zr-ACKR3-mAb uptake in high-ACKR3-expressing tumors. SPECT imaging of (125)I-ACKR3-mAb showed the versatility of ACKR3-mAb for in vivo monitoring of ACKR3 expression.ConclusionData from this study suggest ACKR3 to be a viable diagnostic marker and demonstrate the utility of radiolabeled ACKR3-mAb for in vivo visualization of ACKR3-overexpressing malignancies.

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

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