hIL‐7‐hyFc, A Long‐Acting IL‐7, Increased Absolute Lymphocyte Count in Healthy Subjects

A low lymphocyte count puts immune-compromised patients at risk of mortality. hIL-7-hyFc is a homodimeric interleukin-7 (IL-7), a potent T-cell amplifier, fused to the hybridizing IgD/IgG4 immunoglobulin domain. We performed a randomized, double-blind, placebo-controlled, dose-escalation, phase I study to assess the pharmacokinetic, pharmacodynamic, safety, tolerability, and immunogenicity profiles of hIL-7-hyFc administered s.c. and i.m. to healthy volunteers. Thirty subjects randomly received hIL-7-hyFc or its matching placebo in an 8:2 ratio at 20, 60 mu g/kg s.c., or 60 mu g/kg i.m. The hIL-7-hyFc was slowly absorbed and its terminal half-life was 63.26 hours after i.m. administration. The hIL-7-hyFc increased absolute lymphocyte count, mostly in T-cells, which peaked 3 weeks after administration and then lasted for several additional weeks. The hIL-7-hyFc was well-tolerated after a single s.c. and i.m. administration. Injection site reaction was the most common treatment-emergent adverse event, which resolved spontaneously without treatment. The hIL-7-hyFc can be developed into a beneficial treatment option for patients with compromised T-cell immunity. This trial was registered at as #NCT02860715.11Nsciescopu

Adenoviral transgene ubiquitination enhances mouse immunization and class I presentation by human dendritic cells

International audienceTherapeutic vaccination aims at a strong stimulation of antigen-specific CD8(+) T-cells, so that they differentiate into effectors active in vivo against antigenic targets. Two adenovirus vectors ( Ad) encoding two HLA-A*0201-restricted HIV epitope sequences (pol 476 and pol 589) were constructed. The Ad differ by the presence or absence of a ubiquitin monomer sequence (AdUb(+) and AdUb(-)). The effect of transgene product ubiquitination was analyzed on (1) in vivo, the immunization of Ad vaccinated HLA-A* 0201 humanized HHD mice and ( 2) in vitro, the presentation of the transgene encoded peptides by transduced human dendritic cells ( DC). In vivo, we found that immunization of humanized HHD mice with AdUb(+) elicited a transgene product-specific ;interferon (INF)-gamma CD8(+) T-cell response detectable by enzyme-linked immunospot (ELISPOT), whereas the AdUb(-) construction did not. Antigen-specific cytotoxic T lymphocytes (CTL) were also generated in HHD mice immunized with AdUb(+) and not with AdUb(-). In vitro, using human AdUb(+)-transduced DC, a sizeable expansion of pol 476 and pol 589 tetramer positive CD8(+) T cells as well as CD8(+) CTL were obtained in healthy donors. Compared to AdUb(-)-transduced DC, AdUb(+)-transduced DC triggered a higher number of pol 476-specific IFN-gamma-secreting CD8(+) T cells. In agreement, AdUb(+) transduced DC, used as target in a Cr-51-release assay, were more efficiently lysed by peptide-specific CTL than AdUb(-)-transduced DC. In conclusion, the addition of an ubiquitin sequence to the adenoviral transgene, used as an antigen source, resulted in both in vivo enhanced CD8(+) T-cell immunogenicity in HHD mice and in vitro increased HLA class I-restricted presentation of encoded peptides by human DC