Peptide-loaded tolerogenic PS-liposomes
Tolerogenics ToleroAIT technology
Peptide-based immunotheapy
Allergen-specific immunotherapy (AIT) offers the promise of restoring lasting immunological tolerance to allergens. However, there are major concerns with regard to efficacy, safety and compliance of patients with current SIT modalities.
Several new therapeutic approaches have been developed in the recent past and are currently evaluated in clinical trials. One of the most promising approaches utilizes short allergen-derived T cell epitope peptides for intradermal or transdermal administration.
The most important advantage of this technology is the elimination of safety concerns, since short allergen-derived peptides are not able to cross-link allergen-specific IgE antibodies and, therefore, do not cause IgE-mediated side effects.
Uptake and presentation of peptides
Various experimental and clinical studies have demonstrated that short allergen/autoantigen-derived T-cell-epitope peptides are capable of improving allergy and autoimmune diseases. However, uptake and presentation of short peptides by APC is insufficient.
The preferred way of APC to present peptides is uptake by endocytosis with subsequent intracellular binding to MHC molecules (see pathway 1a-c). Alternatively, it has been shown that extracellular replacement of MHC-bound peptides is possible (see pathway 2). Furthermore, binding of extracellular peptides to surface-exposed peptide-free MHC molecules has been described.
However, all of these presentation mechanisms are not efficient. Endocytotic uptake of small peptides by APC is poor, surface-attached proteases interfere with the extracellular replacement of MHC-bound peptides, and peptide-free MHC molecules on the cellular surface are rare.
Clinical efficacy of peptide-based immunotherapy
Although promising phase II clinical trials with short allergen-derived T cell epitope peptides have been reported, a recent phase III clinical field study has revealed disappointing results (Bloomberg 2016, Cat allergy immunotherapy phase III results, Circassia 2016).
Most likely, the limited clinical efficacy is a result of poor uptake and presentation of intradermally or transdermally administred short peptides by APC. Theoretically, the limited uptake can be compensated by higher doses of peptides, but this concept works only to a certain extent. As revealed in one clinical study, intradermal injection of a 10-fold higher dose of peptides induced late asthmatic responses in some patients which was attributed to an enhanced cytokine release from peptide-stimulated T cells (Haselden et al., 1999, J. Exp. Med. 189:1885-1894).
Peptide delivery system of Tolerogenics
Tolerogenics has developed a novel patent-protected technology for a most efficient uptake and presentation by APC. The technology is based on hydrogel-embedded tolerizing phosphatidylserine (PS)-liposomes, containing sort allergen-derived T cell epitope peptides.
Most important features of the tolerizing PS-liposome technology of Tolerogenics include:
- The hydrogel technology serves as depot and provides for a sustained release of peptide-loaded PS-liposomes for a period of at least 3 days which is important for efficient tolerogenic priming of antigen presenting cells (APCs), since the development of immunologic memory requires the engagement of the T cell receptor (TCR) over 12-48 h.
- Hydrogel-embedded PS-liposomes mimic the anti-inflammatory effect of apoptotic cells since surface-exposed phosphatidylserine (PS) represents the most important ‘eat-me’ signal of apoptotic cells for APCs. In addition PS can act as a toleogenic signal for dendritic cells (DCs). As a result, peptide-loaded PS-liposomes target directly APCs including DCs and macrophages, both of which play a dominant role in determining the outcome of immune responses.
- Phagocytosis of PS-liposomes with encapsulated allergen-derived T cell peptides by DCs and macrophages guarantees most efficient uptake and presentation of the allergen-derived peptides by APCs.
- Peptides encapsulated in PS-liposomes are protected against proteolytic degradation by surface-attached proteases.
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