Dataset Information

A novel format for recombinant antibody-interleukin-2 fusion proteins exhibits superior tumor-targeting properties in vivo.

ABSTRACT: The targeted delivery of interleukin-2 to the tumor is gaining attention as an avenue to potentiate the action of T and NK cells at the site of disease. We have previously described the fusion of the L19 antibody, specific to the EDB domain of fibronectin, with human interleukin-2, using a non-covalent homodimeric diabody format. Here, we describe four novel formats for the L19-IL2 fusion, featuring different arrangements of antibody and IL2. A comparative quantitative biodistribution analysis in tumor-bearing mice using radioiodinated proteins revealed that the novel format (L19L19-IL2, with the antibody in single-chain diabody format) exhibited the best biodistribution results. In vitro assays on peripheral blood mononuclear cells showed a decrease activation of regulatory T cells when single IL2 domain was used. In vivo, both L19-IL2 and L19L19-IL2 inhibited tumor growth in immunocompetent mouse models of cancer. T-cell analysis revealed similar levels of CD4+ and FoxP3+ cells, with an expansion of the CD8+ T cell in mice treated with L19-IL2 and L19L19-IL2. The percentage of CD4+ regulatory T cells was markedly decreased with L19L19-IL2 combined with a mouse-specific PD-1 blocker. Collectively, these data indicate that the new L19L19-IL2 format exhibits favorable tumor-homing properties and mediates a potent anti-cancer activity in vivo.

SUBMITTER: Ongaro T

PROVIDER: S-EPMC7566808 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A novel format for recombinant antibody-interleukin-2 fusion proteins exhibits superior tumor-targeting properties <i>in vivo</i>.

Ongaro Tiziano T Gouyou Baptiste B Stringhini Marco M Corbellari Riccardo R Neri Dario D Villa Alessandra A

Oncotarget 20201013 41

The targeted delivery of interleukin-2 to the tumor is gaining attention as an avenue to potentiate the action of T and NK cells at the site of disease. We have previously described the fusion of the L19 antibody, specific to the EDB domain of fibronectin, with human interleukin-2, using a non-covalent homodimeric diabody format. Here, we describe four novel formats for the L19-IL2 fusion, featuring different arrangements of antibody and IL2. A comparative quantitative biodistribution analysis i ...[more]

PMID: 33110477

Similar Datasets

Project description:Interleukin-1 beta (IL-1?) is an inflammatory cytokine that is secreted in response to inflammasome activation by innate microbe-sensing pathways. Although some retroviruses can trigger IL-1? secretion through the DNA-sensing molecule IFI16, the effect of IL-1? on the course of infection is unknown. To test whether IL-1? secretion affects retroviral replication in vivo, I constructed a novel murine leukemia virus strain (FMLV-IL-1?) that encodes the mature form of IL-1?. This virus replicated with kinetics similar to that of wild-type virus in tissue culture but caused a dramatically more aggressive infection of both C57BL/6 and BALB/c mice. By 7 days postinfection (PI), mice infected with FMLV-IL-1? exhibited splenomegaly and viral loads 300-fold higher than those in mice infected with wild-type FMLV. Furthermore, the enlarged spleens of FMLV-IL-1?-infected mice correlated with a large expansion of Gr-1(+) CD11b(+) myeloid-derived suppressor cells, as well as elevated levels of immune activation. Although FMLV-IL-1? infection was controlled by C57BL/6 mice by 14 days p.i., FMLV-IL-1? was able to establish a significant persistent infection and immune activation in BALB/c mice. These results demonstrate that IL-1? secretion is a powerful positive regulator of retroviral infection and that FMLV-IL-1? represents a new model of proinflammatory retroviral infection.Interleukin-1 beta (IL-1?) is an inflammatory cytokine released in response to activation of innate pathogen-sensing pathways during microbial infection. To examine the potential impact of IL-1? on retroviral replication in vivo, I constructed a novel mouse retrovirus strain (FMLV-IL-1?) that encodes IL-1? and promotes abundant IL-1? secretion from infected cells. This virus replicates with normal kinetics in cultured cells but displays a dramatically enhanced ability to replicate in mice and caused persistent infection and immune activation in the BALB/c strain of mice. These results establish IL-1? as a positive regulator of retroviral replication and suggest that targeting this pathway may have therapeutic benefits in infections with proinflammatory retroviruses. This virus can also be used to further study the impact of inflammatory pathways on retroviral infection.

Dataset Information

A novel format for recombinant antibody-interleukin-2 fusion proteins exhibits superior tumor-targeting properties in vivo.

Publications

A novel format for recombinant antibody-interleukin-2 fusion proteins exhibits superior tumor-targeting properties <i>in vivo</i>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets