Modular complement assemblies for mitigating inflammatory conditions

Abstract

Complement protein C3dg, a key linkage between innate and adaptive immunity, is capable of stimulating both humoral and cell-mediated immune responses, leading to considerable interest in its use as a molecular adjuvant. However, the potential of C3dg as an adjuvant is limited without ways of controllably assembling multiple copies of it into vaccine platforms. Here, we report a strategy to assemble C3dg into supramolecular nanofibers with excellent compositional control, using β-tail fusion tags. These assemblies were investigated as therapeutic active immunotherapies, which may offer advantages over existing biologics, particularly toward chronic inflammatory diseases. Supramolecular assemblies based on the Q11 peptide system containing β-tail–tagged C3dg, B cell epitopes from TNF, and the universal T cell epitope PADRE raised strong antibody responses against both TNF and C3dg, and prophylactic immunization with these materials significantly improved protection in a lethal TNF-mediated inflammation model. Additionally, in a murine model of psoriasis induced by imiquimod, the C3dg-adjuvanted nanofiber vaccine performed as well as anti-TNF monoclonal antibodies. Nanofibers containing only β-tail–C3dg and lacking the TNF B cell epitope also showed improvements in both models, suggesting that supramolecular C3dg, by itself, played an important therapeutic role. We observed that immunization with β-tail–C3dg caused the expansion of an autoreactive C3dg-specific T cell population, which may act to dampen the immune response, preventing excessive inflammation. These findings indicate that molecular assemblies displaying C3dg warrant further development as active immunotherapies.

Self-assembling peptide nanofiber HIV vaccine elicits robust vaccine-induced antibody functions and modulates Fc glycosylation

“…We previously demonstrated that a peptide termed β tail can slowly transition from an α helix to a β sheet conformation and coassemble with Q11 nanofibers even when conjugated to a folded protein ( 28 , 35 ). With such property, β tail serves as a versatile tool for incorporating folded protein antigens in nanofibers formed by self-assembling β sheet peptides.…”

Biomaterial engineering strategies for B cell immunity modulations

“…Utilizing the adjuvanting effect of the complement protein, C3dg, Hainline et al designed an anti-TNF vaccine formed by Q11 nanofibers co-assembled with C3dg bearing a beta-tail handle (βtail-C3dg). 199,200 C3dg Fig. 4 Overview of current strategies to integrate T cell help for B cell immunity.…”

Chemical and biological conjugation strategies for the development of multivalent protein vaccine nanoparticles

“…[ 100 ] Aside from oncoantigens, Q11 has been used for a wide variety of antigens including viral antigens such as HIV gp120 envelope glycoprotein [ 101,102 ] and self-antigens such as anti-TNF B cell epitopes. [ 103,104 ] When antigens were used in conjunction with T cell epitopes and adjuvants, such as STING and TLR9 agonists [ 105 ] or complement protein C3dg 104 , enhanced immunogenicity was seen in immunized mice. Q11 has been shown to be a versatile platform to display various antigens for different vaccine applications.…”