Immunomodulation profile of the biosimilar trastuzumab MYL-1401O in a bioequivalence phase I study.

The initial Phase-I single centre, single dose, randomized, double-blind, cross-over study was planned to assess the pharmacokinetic and pharmacodynamic bioequivalence of the trastuzumab biosimilar (MYL-1401O) compared to the reference Herceptin®. Their respective immunomodulation profile presented in this paper involved healthy males receiving a single infusion of both monoclonals, separated by a washout period. Sixty parameters were assessed in total, including serum cytokines, peripheral mononuclear cell (PBMC) subsets, cell activation and response to recall antigens and mitogen, pre- and post- infusion, as well as a cytokine release assay (CRA) at baseline. Trastuzumab infusion induced a transient and weak peak of serum IL-6 at 6 h, and a modulation of mononuclear cell subset profile and activation level, notably CD16 + cells. Except for CD8 + T cells, there were no significant differences between Herceptin® and MYL-1401O. In CRA, PBMC stimulated with MYL-1401O or Herceptin® similarly secreted IL-6, TNF-α, IL-1ß, GM-CSF, IFN-γ, and IL-10, but no or low level of IL-2. Interestingly, some observed adverse events correlated with IL-2 and IFN-γ in CRA. MYL-1401O exhibited a very similar immunomodulation profile to Herceptin®, strongly supporting its bioequivalence. This approach may thus be included in a proof-of-concept study. CRA may be used as a predictive assay for the evaluation of clinical monoclonals.

Cellular immunity in healthy volunteers treated with an octavalent conjugate Pseudomonas aeruginosa vaccine.

Humoral immunity in response to an octavalent O-polysaccharide-toxin A conjugate Pseudomonas aeruginosa vaccine is well studied, and a phase III clinical study in cystic fibrosis (CF) patients is currently ongoing. In contrast, little is known about cellular immunity induced by this vaccine. Fifteen healthy volunteers were immunized on days 1 and 60. Parameters of cellular immunity were studied before vaccination on day 1, and on day 74. Analyses included flow cytometry of whole blood and antigen-induced proliferation of and cytokine production by lymphocyte cultures. The effects of immunization on the composition of peripheral blood lymphocytes as determined by flow cytometry were minor. In contrast, after immunization a highly significant increase of proliferation in response to stimulation with detoxified toxin A was noted: the stimulation index rose from 1.4 on day 1 to 42.2 on day 74 (restimulation with 0.4 microg/ml; P = 0.003). Immunization led to significant production of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha by antigen-stimulated lymphocytes. In contrast, no significant induction of interleukin (IL)-4 or IL-10 was observed. In conclusion, immunization of healthy volunteers led to activation of cellular immunity including strong antigen-specific proliferation and cytokine production. In CF patients priming of the cellular immune system towards a Th1-like pattern would be of potential advantage. Therefore, confirmatory analyses in immunized CF patients with and without chronic infection with P. aeruginosa are foreseen.

Cellular immunity in healthy volunteers treated with an octavalent conjugate Pseudomonas aeruginosa vaccine.

Humoral immunity in response to an octavalent O-polysaccharide-toxin A conjugate Pseudomonas aeruginosa vaccine is well studied, and a Phase III clinical study in cystic fibrosis (CF) patients is currently ongoing. In contrast, little is known about cellular immunity induced by this vaccine. Fifteen healthy volunteers were immunized on days 1 and 60. Parameters of cellular immunity were studied before vaccination on day 1, and on day 74. Analyses included flow cytometry of whole blood, and antigen-induced proliferation of and cytokine production by lymphocyte cultures. The effects of immunization on the composition of peripheral blood lymphocytes as determined by flow cytometry were minor. In contrast, after immunization a highly significant increase of proliferation in response to stimulation with detoxified toxin A was noted: the stimulation index rose from 1.4 on day 1 to 42.2 on day 74 (restimulation with 0.4 microg/ml; P = 0.003). Immunization led to significant production of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha by antigen-stimulated lymphocytes. In contrast, no significant induction of interleukin (IL)-4 or IL-10 was observed. In conclusion, immunization of healthy volunteers led to activation of cellular immunity including strong antigen-specific proliferation and cytokine production. In CF patients priming of the cellular immune system towards a Th1-like pattern would be of potential advantage. Therefore, confirmatory analyses in immunized CF patients with and without chronic infection with P. aeruginosa are foreseen.