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Cross-Linked Peptide Nanoclusters for Delivery of Oncofetal Antigen as a Cancer Vaccine
journal contribution
posted on 2018-02-12, 21:07 authored by Alexandra
N. Tsoras, Julie A. ChampionPeptide
subunit vaccines are desirable because they increase control
over the immune response and safety of the vaccine by reducing the
risk of off-target responses to molecules other than the target antigen.
The immunogenicity of most peptides, however, is low. Peptide nanoclusters
(PNC) are proposed as a subunit peptide vaccine delivery system made
completely of cross-linked peptide antigen that could improve the
immunogenicity of a peptide vaccine. Proof of concept is demonstrated
with oncofetal antigen (OFA), an immature laminin receptor protein
expressed by many hematologic cancer cells but not by healthy cells.
Peptide epitopes from this protein, called OFA 1, 2, and 3, were synthesized
into PNC as a potential cancer peptide vaccine delivery system. PNC
were formed by desolvation and stabilized with disulfide bonds using
a trithiol cross-linker. Cysteines were added to the C-terminus of
each peptide to assist in this cross-linking step, denoted OFA 1C,
2C, and 3C PNC. OFA 2C was found to form the smallest PNC, 148 ±
15 nm in diameter and stable in solution. This size is in the range
where particles are readily internalized by dendritic cells (DCs)
and may also passively diffuse to regional lymph nodes. OFA 2C PNC
and soluble OFA 2C were internalized similarly by DCs in vitro, but only PNC resulted in significant peptide presentation by DCs.
This indicates the potential for PNC to improve immune activation
against this antigen. Additionally, PNC displayed higher retention
at the intradermal injection site in vivo than soluble
peptide, allowing more time to interact with DCs in an area of increased
DC activity. While offering traditional nanoparticle benefits such
as increased DC recognition, slower diffusion, and potential for multivalent
cellular interactions, PNC also maximize antigen delivered per particle
while minimizing off-target material delivery because the antigens
are the main building blocks of the particle. With these properties,
PNC are a delivery system with potential to increase peptide subunit
vaccine immunogenicity for OFA and other peptide antigens.
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Keywords
subunit peptide vaccine delivery systemtarget antigenintradermal injection site2 Ccancer peptide vaccine delivery systemOFA 2 C PNCOFA 1 Ccross-linked peptide antigendisulfide bondsbuilding blocksOncofetal Antigendelivery systemlymph nodesPeptide epitopesDC recognitionincrease peptide subunit vaccine immunogenicitypeptide antigenspeptide presentationoff-target responsesoff-target material deliveryOFA 2 Concofetal antigencross-linking stephematologic cancer cellsDC activityPeptide nanoclustersCross-Linked Peptide Nanoclusters3 C PNCnanoparticle benefitstrithiol cross-linkerpeptide vaccinelaminin receptor proteinincrease controlCancer Vaccine Peptide subunit vaccinesdendritic cells
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