Thymosin alpha 1 (trade name Zadaxin) is a 28 amino acid immune-stimulating peptide, which was originally isolated from thymic
tissue, and is now produced by solid-phase peptide synthesis. Thymosin has been shown to activate toll-like receptor 9 (TLR9),
a cell-surface receptor that plays a key role in triggering the body's innate and adaptive immune responses, allowing significant
increases in antibody production and clearance of viral infections. In preclinical studies, treatment with thymosin led to
increased influenza-specific cytotoxic T lymphocyte (CTL) responses following vaccination. In a Phase 2 clinical study, treatment
with biweekly doses of thymosin after vaccination was shown to decrease the incidence of influenza in elderly subjects from
19% in patients receiving influenza vaccine alone to 6% in patients receiving vaccine in combination with thymosin alpha 1
(p = 0.002). Thymosin was also shown to increase the antibody response to influenza vaccines in a number of clinical studies.
These data support the use of thymosin alpha 1 to increase response to vaccination.
As exemplified by the current outbreak of novel H1N1 Influenza A (swine flu), there is an urgent need for novel vaccine-enhancing
compounds that could expand the available vaccine supply, as well as potentially broaden the response to a vaccine across
multiple virus strains. A further and perhaps even more important need may exist in the treatment of historically difficult-to-treat
populations with newly developed vaccines. These include the elderly and persons immune-suppressed by treatment with chemotherapy
or other invasive procedures like dialysis.
SciClone Pharmaceuticals, Inc.
Thymosin alpha 1 (trade name Zadaxin) is a naturally-circulating 28 amino acid immune-stimulating peptide that has shown promise
in enhancing the response to the influenza vaccine. Originally isolated from bovine thymus material, referred to as thymic
fraction 5 (TF-5),1 thymosin alpha 1 is currently produced by solid-phase peptide synthesis and is commercially available in over 30 countries
Over decades of research, thymosin alpha 1 has been shown to have a number of immunomodulating activities, centered primarily
on augmentation of T-cell function. It has been shown to promote T-cell differentiation and maturation;2–7 increase natural killer (NK)-cell activity,8–10 production of interferon (IFN)-alpha, interleukin (IL)-2, and IL-3, expression of IL-2 receptor following activation by
mitogens or antigens,8,11–17 production of migration inhibitory factor (MIF),18 and antibody response to T-cell–dependent antigens;19–21 and activate dendritic cell tryptophan catabolism.22,23 Thymosin alpha 1 also has been shown to antagonize dexamethasone-induced apoptosis in thymocytes in vitro.24,25
In vivo administration of thymosin alpha 1 to animals immunosuppressed by chemotherapy, tumor burden, or irradiation showed that
thymosin alpha 1 protects against cytotoxic damage to bone marrow, tumor progression, and opportunistic infections, thereby
increasing survival time and number of survivors.26–28 (see also 5,6,29,30) Many of the in vitro and in vivo effects of thymosin alpha 1 have been interpreted as influences on either differentiation of pluripotent stem cells to thymocytes
or activation of thymocytes into activated T-cells. The pattern of enhanced cytokine production, i.e., IFN-alpha and IL-2,
suggests that thymosin alpha 1 may influence progression to a T-helper 1 (Th1) type of immune response.31
On a subcellular level, thymosin alpha 1 has been shown to activate toll-like receptor 9 (TLR9), a receptor that plays a key
role in triggering the body's innate and adaptive immune responses.22,32–34 TLR9 activation affects various intracellular cell-signaling pathways that have been implicated in thymosin alpha 1's effects.
These include stimulation of the p38 MAPK and NFkappaB signaling pathways, which are important for the maturation of, and
antigen presentation by, dendritic cells.35–38 Together with the macroscopic effects of thymosin alpha 1 described above, these effects on signaling pathways provide a
rationale for why treatment with thymosin alpha 1 could lead to significant responses to vaccination.
Thymosin alpha 1 has an excellent safety profile. Adverse experiences have been infrequent and mild in over 70 studies conducted
under US corporate investigational new drug applications (INDs), physician INDs, trials in foreign countries, and market experience
to date in over 2,500 individuals who have received thymosin alpha 1.39,40 These studies have shown effectiveness in a variety of indications, including response to vaccination (described below)
as well as various types of cancer (melanoma, non-small-cell lung cancer, glioma, head and neck, renal, breast, gastric, and
myelodysplasia) and infectious disease (chronic hepatitis B and C, HIV, primary immune deficiency).