4 research outputs found
Switching the Immunogenicity of Peptide Assemblies Using Surface Properties
Biomaterials created from supramolecular
peptides, proteins, and
their derivatives have been receiving increasing interest for both
immunological applications, such as vaccines and immunotherapies,
as well as ostensibly nonimmunological applications, such as therapeutic
delivery or tissue engineering. However, simple rules for either maximizing
immunogenicity or abolishing it have yet to be elucidated, even though
immunogenicity is a prime consideration for the design of any supramolecular
biomaterial intended for use <i>in vivo</i>. Here, we investigated
a range of physicochemical properties of fibrillized peptide biomaterials,
identifying negative surface charge as a means for completely abolishing
antibody and T cell responses against them in mice, even when they
display a competent epitope. The work was facilitated by the modularity
of the materials, which enabled the generation of a set of co-assembled
fibrillar peptide materials with broad ranges of surface properties.
It was found that negative surface charge, provided <i>via</i> negatively charged amino acid residues, prevented T cell and antibody
responses to antigen-carrying assemblies because it prevented uptake
of the materials by antigen-presenting cells (APCs), which in turn
prevented presentation of the epitope peptide in the APCs’
major histocompatibility class II molecules. Conversely, positive
surface charge augmented the uptake of fibrillized peptides by APCs.
These findings suggest that some surface characteristics, such as
extensive negative charge, should be avoided in vaccine design using
supramolecular peptide assemblies. More importantly, it provides a
strategy to switch off potentially problematic immunogenicity for
using these materials in nonimmunological applications
Self-Assembling Allergen Vaccine Platform Raises Therapeutic Allergen-Specific IgG Responses without Induction of Systemic Allergic Responses
Allergen immunotherapies are often successful at desensitizing
allergic patients but can require life-long dosing and suffer from
frequent adverse events including instances of systemic anaphylaxis,
leading to poor patient compliance and high cost. Allergen vaccines,
in turn, can generate more durable immunological allergen desensitization
with far fewer doses. However, like immunotherapies, allergen vaccines
are often highly reactogenic in allergic patients, hampering their
use in therapeutic settings. In this work, we utilize a peptide-based
self-assembling nanofiber platform to design allergen vaccines against
allergen B-cell epitopes that do not elicit systemic anaphylaxis when
administered subcutaneously to allergic mice. We show that, in contrast
to protein vaccines, nanofiber vaccines prevent leakage of allergen
material into the vascular compartment, a feature that likely underpins
their reduced systemic reactogenicity. Further, we show that our allergen
vaccine platform elicits therapeutic IgG antibody responses capable
of desensitizing allergic mice to allergen-induced Type I hypersensitivity
reactions. Finally, we have demonstrated a proof-of-concept for the
therapeutic potential of nanofiber-based peanut allergen vaccines
directed against peanut allergen-derived epitopes
Modulating Adaptive Immune Responses to Peptide Self-Assemblies
Self-assembling peptides and peptide derivatives have received significant interest for several biomedical applications, including tissue engineering, wound healing, cell delivery, drug delivery, and vaccines. This class of materials has exhibited significant variability in immunogenicity, with many peptides eliciting no detectable antibody responses but others eliciting very strong responses without any supplemental adjuvants. Presently, strategies for either avoiding strong antibody responses or specifically inducing them are not well-developed, even though they are critical for the use of these materials both within tissue engineering and within immunotherapies. Here, we investigated the molecular determinants and immunological mechanisms leading to the significant immunogenicity of the self-assembling peptide OVA-Q11, which has been shown previously to elicit strong antibody responses in mice. We show that these responses can last for at least a year. Using adoptive transfer experiments and T cell knockout models, we found that these strong antibody responses were T cell-dependent, suggesting a route for avoiding or ensuring immunogenicity. Indeed, by deleting amino acid regions in the peptide recognized by T cells, immunogenicity could be significantly diminished. Immunogenicity could also be attenuated by mutating key residues in the self-assembling domain, thus preventing fibrillization. A second self-assembling peptide, KFE8, was also nonimmunogenic, but nanofibers of OVA-KFE8 elicited strong antibody responses similar to OVA-Q11, indicating that the adjuvant action was not dependent on the specific self-assembling peptide sequence. These findings will facilitate the design of self-assembled peptide biomaterials, both for applications where immunogenicity is undesirable and where it is advantageous
A Supramolecular Vaccine Platform Based on α‑Helical Peptide Nanofibers
A supramolecular
peptide vaccine system was designed in which epitope-bearing
peptides self-assemble into elongated nanofibers composed almost entirely
of α-helical structure. The nanofibers were readily internalized
by antigen presenting cells and produced robust antibody, CD4+ T-cell,
and CD8+ T-cell responses without supplemental adjuvants in mice.
Epitopes studied included a cancer B-cell epitope from the epidermal
growth factor receptor class III variant (EGFRvIII), the universal
CD4+ T-cell epitope PADRE, and the model CD8+ T-cell epitope SIINFEKL,
each of which could be incorporated into supramolecular multiepitope
nanofibers in a modular fashion