A Cancer Therapeutic Vaccine based on Clustered Tn‐Antigen Mimetics Induces Strong Antibody‐Mediated Protective Immunity

Abstract

Tumor‐associated carbohydrate antigens (TACAs) are key components of cancer vaccines. A variety of vaccines based on native TACAs such as α‐Tn have shown immunogenicity and protection in preclinical animal studies, however, their weak immunogenicity, low in vivo instability, and poor bioavailability, have discouraged their further evaluations in clinical studies. A new improved vaccine prototype is reported. It is composed of four clustered Tn‐antigen mimetics and a immunogenic peptide epitope that are conjugated to a cyclopeptide carrier. The immunization of mice with this vaccine 1) was safe, 2) induced a strong and long‐lasting Tn‐specific response with IgM/IgG antibodies able to recognize native carbohydrate antigens; 3) produced high titers of IgG1, IgG2a, and IgG3 antibodies; and 4) produced a significant antibody‐dependent regression of tumors and conferred protection. Altogether, these findings pave the way for the clinical development of safe and effective therapeutic vaccines against Tn‐expressing cancers.

Immunological characterization of a rigid α-Tn mimetic on murine iNKT and human NK cells

“…1), decorated with high density of the Tn mimetic 1, induce a specific macrophage activation [41]; ii) the synthetic peptide-based glyco-cluster 4 ( Fig. 1), which provided the multivalent presentation of the mimetic 1, elicits significant IgG/IgM mAb production and protection in mice affected by breast cancer [40]. The overall data confirm that the biological effect of the Tn-mimetic 1 can be modulated by changing the nonglycan portion of the conjugate.…”

“…1), when properly functionalized on the carboxylic group with a suitable architecture, is able to trigger different immune cells and induce specific and long-lasting immune responses [40]. In particular: i) biocompatible and immunogenic iron oxide superparamagnetic nanoparticles 3 ( Fig.…”

“…In particular, the glycolipid 5, which consists of a stearic acid containing glycerol-based phospholipid conjugated to a residue of the Tn-mimetic 1, was chosen because of its ability to be presented by CD1d [42] to induce iNKT cell activation (T-cell-antigen presenting assay). On the contrary, taking into account that the multivalent presentation of 1 is important to modulate the induced immune response [40] the hexavalent glycopeptide 6 was also included in the study. Indeed, the glycopeptide 6 consists, of a cyclopeptide scaffold, termed regioselectively addressable functionalized template (RAFT) [43], where six residues of 1, four on the upper face and two on the lower face of the RAFT, were conjugated to the lysine lateral chains.…”

Strategies for Synthesizing and Enhancing the Immune Response of Cancer Vaccines Based on MUC1 Glycopeptide Antigens

“…In addition to these polymer backbones, some natural backbones that can be modified multivalently have also been used to construct multivalent MUC1 glycopeptides. Renaudet et al [114] . chose a cyclic peptide structure with multiple lysines as the backbone, and connected four tumor‐associated Tn antigens through the amidation reaction of lysine side chains, and then coupled with T‐cell epitope and immune stimulator Pam3CS lipopeptide to form a multivalent tumor vaccine; Recently, Pifferi et al [115] .…”