a Totally Synthetic, Self-Assembling, Adjuvant-Free MUC1 Glycopeptide Vaccine for Cancer Therapy

Abstract

In the development of vaccines for epithelial tumors, the key targets are MUC1 proteins, which have a variable number of tandem repeats (VNTR) bearing tumor-associated carbohydrate antigens (TACAs), such as Tn and STn. A major obstacle in vaccine development is the low immunogenicity of the short MUC1 peptide. To overcome this obstacle, we designed, synthesized, and evaluated several totally synthetic self-adjuvanting vaccine candidates with self-assembly domains. These vaccine candidates aggregated into fibrils and displayed multivalent B-cell epitopes under mild conditions. Glycosylation of Tn antigen on the Thr residue of PDTRP sequence in MUC1 VNTR led to effective immune response. These vaccines elicited a high level antibody response without any adjuvant and induced antibodies that recognized human breast tumor cells. These vaccines appeared to act through a T-cell independent pathway and were associated with the activation of cytotoxic T cells. These fully synthetic, molecularly defined vaccine candidates had several features that hold promise for anticancer therapy.

Active immunotherapy for TNF-mediated inflammation using self-assembled peptide nanofibers

“…Platforms that share structural similarities with Q11 and which may be interesting to study in this regard include other peptides that form into long, high-aspect ratio nanofibers. For example the peptide KFE8 has been explored previously in vaccinations against cocaine addiction [43]; the peptide RADA4 has been explored as a depotforming material in vaccines against hepatitis B [44]; the peptide EAK16 has been investigated in vaccines against HIV [45]; the peptide Ac-AAVVLLLW-COOH has been explored in anticancer vaccines [46]; and Q11 has been explored in applications including malaria [47], influenza [19], S. aureus vaccines [20], and cancer [48]. Other fibrous self-assemblies include those composed of peptide amphiphiles, which have been explored in anticancer vaccines [49] and vaccines against group A streptococcus [50].…”

Self-assembling peptide-based building blocks in medical applications

“…The Q11 peptide (QQKFQFQFEQQ) is able to form fibril structures with functional epitopes or proteins conjugated to them without disrupting the self-assembling capacity [121–123]. The peptide fibers themselves, even when delivered with complete Freund’s adjuvant (CFA), did not raise a detectable immune response.…”

Enhancing the Magnitude of Antibody Responses through Biomaterial Stereochemistry

“…8−12 When a peptide or protein antigen is covalently linked to a selfassembling peptide domain the resulting nanofibers display the antigen on their surface in a multivalent fashion. 8 Immunization with antigen-bearing peptide nanofibers has been shown to be protective in murine models of malaria, 10 cancer, 11 and influenza. 12 Moreover, this phenomenon was not limited to a single self-assembling peptide domain, route of administration, disease model, or mouse strain.…”