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Durable targeting of B-lymphocytes in living mice.

ABSTRACT: Transfer to and enduring expression of genes in B cells has proved a vexing challenge. We report here a novel method for the specific and durable targeting of B lymphocytes in living mice. The method involves generation of lentiviruses pseudotyped with an anti-CD19 antibody. CD19 targeting viruses injected in the spleen of living mice efficiently transduced B cells and plasma cells detected by flow cytometry analysis of GFP expression. Expression of the reporter gene could be detected in the intact animal by external imaging for more than a year and was enhanced by booster immunization. Our method thus enables the specific delivery, expression and localization by external imaging of exogenous genes to the B cells and plasma cells of living individuals.

SUBMITTER: Cascalho M

PROVIDER: S-EPMC6057982 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Durable targeting of B-lymphocytes in living mice.

Cascalho M M Huynh D D Lefferts A R AR Stein L L Lanigan T T Decker J J Shea L D LD Platt J L JL

Scientific reports 20180724 1

Transfer to and enduring expression of genes in B cells has proved a vexing challenge. We report here a novel method for the specific and durable targeting of B lymphocytes in living mice. The method involves generation of lentiviruses pseudotyped with an anti-CD19 antibody. CD19 targeting viruses injected in the spleen of living mice efficiently transduced B cells and plasma cells detected by flow cytometry analysis of GFP expression. Expression of the reporter gene could be detected in the int ...[more]

PMID: 30042489

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Project description:BackgroundGlioblastoma (GB), the most aggressive brain cancer, remains a critical clinical challenge due to its resistance to conventional treatments. Here, we introduce a locoregional targeted-α-therapy (TAT) with the rat monoclonal antibody 9E7.4 targeting murine syndecan-1 (SDC1) coupled to the α-emitter radionuclide astatine-211 (211At-9E7.4).MethodsWe orthotopically transplanted 50,000 GL261 cells of murine GB into the right striatum of syngeneic female C57BL/6JRj mice using stereotaxis. After MRI validation of tumour presence at day 11, TAT was injected at the same coordinates. Biodistribution, efficacy, toxicity, local and systemic responses were assessed following application of this protocol. The 9E7.4 monoclonal antibody was labelled with iodine-125 (125I) for biodistribution and with astatine-211 (211At) for the other experiments.FindingsThe 211At-9E7.4 TAT demonstrated robust efficacy in reducing orthotopic tumours and achieved improved survival rates in the C57BL/6JRj model, reaching up to 70% with a minimal activity of 100 kBq. Targeting SDC1 ensured the cerebral retention of 211At over an optimal time window, enabling low-activity administration with a minimal toxicity profile. Moreover, TAT substantially reduced the occurrence of secondary tumours and provided resistance to new tumour development after contralateral rechallenge, mediated through the activation of central and effector memory T cells.InterpretationThe locoregional 211At-9E7.4 TAT stands as one of the most efficient TAT across all preclinical GB models. This study validates SDC1 as a pertinent therapeutic target for GB and underscores 211At-9E7.4 TAT as a promising advancement to improve the treatment and quality of life for patients with GB.FundingThis work was funded by the French National Agency for Research (ANR) "France 2030 Investment Plan" Labex Iron [ANR-11-LABX-18-01], The SIRIC ILIAD [INCa-DGOS-INSERM-18011], the French program "Infrastructure d'Avenir en Biologie-Santé" (France Life Imaging) [ANR-11-INBS-0006], the PIA3 of the ANR, integrated to the "France 2030 Investment Plan" [ANR-21-RHUS-0012], and support from Inviscan SAS (Strasbourg, France). It was also related to: the ANR under the frame of EuroNanoMed III (project GLIOSILK) [ANR-19-ENM3-0003-01]; the "Région Pays-de-la-Loire" under the frame of the Target'In project; the "Ligue Nationale contre le Cancer" and the "Comité Départemental de Maine-et-Loire de la Ligue contre le Cancer" (CD49) under the frame of the FusTarG project and the "Tumour targeting, imaging and radio-therapies network" of the "Cancéropôle Grand-Ouest" (France). This work was also funded by the Institut National de la Santé et de la Recherche Médicale (INSERM), the University of Nantes, and the University of Angers.

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Durable targeting of B-lymphocytes in living mice.

Publications

Durable targeting of B-lymphocytes in living mice.

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