Transdermal targeted delivery for immunomodulation
Dr Christoph Rademacher, Max-Planck Institute of Colloids and Interfaces ; Dr Robert Wawrzinek, Max-Planck Institute of Colloids and Interfaces; Dr Eike-Christian Wamhoff, Max-Planck Institute of Colloids and Interfaces; Dr Jessica Schulze, Max-Planck Institute of Colloids and Interfaces; Prof. Oliver Seitz, Humboldt University ; Gunnar Bachem, Humboldt University
Max Planck Innovation
Activating the body’s own immune system to fight pathogens or treat autoimmune diseases is highly attractive but requires an effective and controlled delivery of antigen to immune modulation cells. Traditionally, therapeutics are administered by injection into blood or skin and passively find their way to their target cells – after most of the drug has already been cleared or was taken up by numerous off-target cells. All this leads to a low clinical efficacy, in turn requires administration of higher dosages and causes unwanted side effects. On the other hand, targeted delivery to specific immune cells promises to overcome these drawbacks. However, this is difficult to achieve since available ligands to selectively target certain immune cells are sparse. Moreover, finding an appropriate administration route that quickly and effectively reaches the targeted cells can be equally challenging.
We use an innovative system to selectively deliver antigen (i.e. protein, peptide, mRNA) to a specific subset of skin-residing immune cells, called Langerhans cells (LCs). The system is comprised of a liposomal vehicle, decorated with the first LC specific small molecule ligand and protects its antigen cargo until uptake by LCs. Due to an ideal ligand affinity the cargo can be released into the cell without blocking the recycling receptor for additional uptake cycles (as antibodies would do). This accumulates large quantities of antigen which are eventually presented to T cells in the lymph nodes and trigger an according immune response against the antigen. Since LCs are predominantly found in the epidermis, the system is administered via a transdermal route (e.g. microneedle patch) yielding a highly effective activation of antigen-specific T-cells along with reduced drug loads and consequently fewer side effects. In a different setup we hope to exploit these mechanisms to address autoimmune diseases.
Since this versatile delivery system can be used for potentially any antigen-specific immune response, it is compatible with next gen mRNA cancer immune therapies, therapeutic and prophylactic vaccines as well as for addressing Langerhans Cell histiocytois and autoimmunity. Immuno-oncologic approaches for modulation of T cell responses (CAR-T, BiTE or DC vaccines) today all require ex vivo manipulation of T cells or DCs - a production step that is rate-limiting and expensive as it depends on a substantial degree of highly skilled manual labor. The herein described approach is an in vivo vaccine strategy without the need of ex vivo manipulation. A further opportunity in prophylactic vaccines is to eliminate the need for a cold chain by replacing vaccines using inactivated viruses, live attenuated or recombinant viruses with RNA-based vaccines; stably packed as ready-to-use needle-free (microneedle) patches.
Several proof-of-concepta have been shown in model and primary cell lines, human skin explants and first in vivo experiments with transgenic mice, expressing the human receptor that recognizes the targeting ligand. Further preclinical evaluations, including other animal species and indications are currently ongoing.
A European priority establishing patent application was submitted in January 2018 and followed by a PCT application in 2019, which entered the nationalisation phase in 2020.
Wamhoff et al., ACS Cent. Sci. 2019, doi: 10.1021/acscentsci.9b00093