Delivery Systems for Immunomodulatory Proteins and Peptides

Abstract

Polypeptide and protein immunomodulators are subject to absorption, biodistribution, metabolism and degradation at sites and rates which may not permit effective interactions with components of the immune system. Drug carrier technology can overcome some of these obstacles. Because of the lipid and particulate nature of liposomes, increased delivery of immunomodulators to lymphatics, lymph nodes, lymphatic organs and concentrations of macrophages is possible when an immunomodulator is associated with a liposome. Interleukin-2 (IL-2) liposomes have been shown to have less toxicity and increased immunotherapeutic effects in a number of model systems and are currently in human clinical trials. Local routes such as aerosol delivery to the lung are particularly well suited to use with liposomes containing immunomodulators. Polypeptides can also enhance the interaction of an immunomodulator with the immune system via increased immunostimulation; this can provide a means to enhance oral delivery and to achieve depot effects. Polysaccharide microspheres have been shown to be effective biodegradable carriers of immunomodulators. Finally, genetically engineered bacteria, viruses and mammalian cells may function as delivery systems for immunomodulatory peptides and proteins. Attenuated Salmonella strains can deliver immunomodulators to the gut-associated lymphoid tissue, liver and spleen. In mouse experiments using tumour cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF), irradiated tumour preparations produced GM-CSF and were capable of eliciting effective cell-mediated immune responses, including destruction and elimination of tumour as well as resistance to tumour challenge (i.e. memory response). A wide variety of immunomodulators have been tested using this strategy; IL-2 and GM-CSF are among the most potent inducers of both cell-mediated effector and memory responses. In summary, use of delivery systems can significantly enhance the immunomodulatory potential of polypeptides and proteins.

Liposome‐entrapped D. pteronyssinus vaccination in mild asthma patients: effect of 1‐year double‐blind, placebo‐controlled trial on inflammation, bronchial hyper‐responsiveness and immediate and late bronchial responses to the allergen

“…Liposomes are non‐toxic and biodegradable vehicles with the ability to both sustain release of multiple therapeutic agents, including allergens, and to bias the immune response towards a Th1‐type [17–19]. These features raise the possibility of using liposomes as AV adjuvants.…”

“…Liposomes are small vesicles of non‐toxic, biodegradable and naturally occurring lipids, that act as potent immunological adjuvants with little allergenic potential [17], inducing a Th1‐shift of the immune response [18]. Liposomes have a notable depot effect after subcutaneous injection [17] and increase the delivery of proteins to lymphatic vessels, lymph nodes and macrophages [19]. These properties suggest a role for liposomes as AV adjuvants.…”

Literature review in support of adjuvanticity/immunogenicity assessment of proteins

“…Interestingly, proteins and peptides have been shown to enhance the interaction of an immunomodulator with the IS via increased immunostimulation and this behavior, in the context of drug delivery, is used to enhance oral delivery and achieve depot effects 104 . Relevant examples of intrinsic allergen-associated immunomodulators are lipocalins, lectins, caseins, iron chelators, plant lipid transfer protein or glycoproteins; extrinsic immunomodulators are toll-like receptor ligands, lipopolysaccharides, beta-glucan and chitin 32 .…”

Allergen immunotherapy: therapeutic vaccines for allergic diseases

“…Drug carrier technology may overcome some of these obstacles. Because of the lipid and particulate nature of liposomes, increased delivery of proteins to lymphatics, lymph nodes, and macrophages may be possible when a protein is associated with a liposome (388). Such an approach is currently under investigation in humans, but definitive results are still lacking (56,57,389).…”