IMP321 (sLAG-3) safety and T cell response potentiation using an influenza vaccine as a model antigen: A single-blind phase I study
Introduction
Soluble LAG-3 (sLAG-3) binds to MHC class II molecules and induces dendritic cells (DC) to mature and migrate to secondary lymphoid organs where they can prime naive CD4-helper and CD8-cytotoxic T cells [1], [2], [3], leading to tumour rejection [4], [5], [6]. This maturation effect is dependent upon the specific binding of sLAG-3 to MHC class II molecules located in membrane lipid raft microdomains [7]. The immunostimulatory activity of sLAG-3 in inducing tumour-associated human antigen-specific CD8+ T cell responses [8], supports the use of this recombinant protein as a promising candidate adjuvant for therapeutic vaccination.
In the present study, we report on the clinical and biological effects, and safety evaluation of IMP321, a GMP-grade sLAG-3 (hLAG-3Ig) protein, used alone or mixed with a commercial influenza vaccine (Agrippal®). The results of this first proof-of-concept clinical study in healthy volunteers using influenza hemagglutinin (HA) as a model antigen with known strong skin reactivity has allowed the completion of a safety and immunogenicity package for this first-in-class product.
Section snippets
Study design and subject selection
This single-blind controlled phase I study was conducted at the Aster-Cephac S.A. facility in Paris (France). Ethical Review Board approval was obtained and each patient provided voluntary informed consent. Eligible subjects were healthy adult male volunteers, aged 18–40, not vaccinated against flu in the last 2 years. Other exclusion criteria included liver enzyme levels outside the normal range, chronic HIV, HBV or HCV infection, or evidence of any other clinically significant acute or
Population characteristics
The clinical part of this study was conducted between April 2005 and August 2005. A total of 93 subjects were screened, of which 60 were enrolled and received one dose of vaccine. Baseline characteristics and demographics were evenly distributed among the ten cohorts (see Table 1, Table 2), with the exception of race in the control Agrippal® group (Table 2). All subjects but one completed the study.
Safety and tolerability
Overall, IMP321 injected alone or in combination with Agrippal® was characterised by a good
Discussion
Half of the subjects injected with the flu vaccine experienced some AEs but the frequency and intensity for these AEs were not increased in the groups co-injected with 3, 10, 30 or 100 μg IMP321, establishing a first relevant safety package for IMP321 tested together with an “inflammatory-type” vaccine. Also, an s.c. injection of IMP321 did not induce specific antibodies in healthy individuals and this is another important finding in terms of safety, since anti-IMP321 antibodies could possibly
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