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Toxicology and biodistribution of AdAPT-001, a replication-competent type 5 adenovirus with a trap for the immunosuppressive cytokine, TGF-beta.

ABSTRACT: Transgene-enhanced oncolytic adenoviruses represent a promising novel therapeutic option for the treatment of cancer. A Phase 1 clinical trial featuring AdAPT-001 is ongoing (NCT04673942). AdAPT-001, a type 5 adenovirus, which carries a TGF-β trap transgene that neutralizes the immunosuppressive cytokine, TGF-β, has been shown in an immunocompetent mouse model to eradicate both locally injected and non-injected tumors. Single dose biodistribution of the TGF-β trap transgene was also evaluated in tumor bearing mice, providing an explanation for systemic activity. The biodistribution and toxicity of a single administration of mouse AdAPT-001 (mAdAPT-001) in 129S1 immunocompetent mice bearing ADS-12 tumors (mouse lung carcinoma) were assessed. mAdAPT-001 was injected intratumorally and intravenously in groups of 25 mice each at varying dose levels. Soluble TGF-β trap was detected in the serum using ELISA. A single AdAPT-001 injection resulted in non-negligible long-term TGF-β trap persistence in the serum over the 14-day study after intravenous and intratumoral administration. No TGF-β-related toxicity was observed. At clinically relevant doses, AdAPT-001 was safe and well tolerated. Systemic levels of the TGF-β trap transgene were observed from both local and intravenous dosing.

SUBMITTER: Larson C

PROVIDER: S-EPMC8569352 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Toxicology and biodistribution of AdAPT-001, a replication-competent type 5 adenovirus with a trap for the immunosuppressive cytokine, TGF-beta.

Larson Christopher C Oronsky Bryan B Abrouk Nacer E NE Oronsky Arnold A Reid Tony R TR

American journal of cancer research 20211015 10

Transgene-enhanced oncolytic adenoviruses represent a promising novel therapeutic option for the treatment of cancer. A Phase 1 clinical trial featuring AdAPT-001 is ongoing (NCT04673942). AdAPT-001, a type 5 adenovirus, which carries a TGF-β trap transgene that neutralizes the immunosuppressive cytokine, TGF-β, has been shown in an immunocompetent mouse model to eradicate both locally injected and non-injected tumors. Single dose biodistribution of the TGF-β trap transgene was also evaluated in ...[more]

PMID: 34765319

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Project description:A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid ?-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×10(5) vg/?g genomic DNA (gDNA), while uninjected sites had up to 1.0×10(4) vg/?g gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0×10(6) vg/?g gDNA, followed by a decrease to 1.0×10(3) vg/?g gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections.

Dataset Information

Toxicology and biodistribution of AdAPT-001, a replication-competent type 5 adenovirus with a trap for the immunosuppressive cytokine, TGF-beta.

Publications

Toxicology and biodistribution of AdAPT-001, a replication-competent type 5 adenovirus with a trap for the immunosuppressive cytokine, TGF-beta.

Similar Datasets

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