---
title: "Synthetic Antigen Design"
description: "How nCage builds vaccines that stay ahead of a changing pathogen: a conserved epitope, isolated from the protein around it, held on a designed scaffold and displayed on a TRAP-cage."
url: https://www.ncage.org/en/antigen-design
language: en
site: nCage Therapeutics
---

# Synthetic Antigen Design

How nCage builds vaccines that stay ahead of a changing pathogen: a conserved epitope, isolated from the protein around it, held on a designed scaffold and displayed on a TRAP-cage.

> The pathogen varies. The antigen does not. That is how a synthetic antigen outruns antigenic variation.

## Most of the surface changes. A small part cannot.

Pathogen surface proteins are under continuous selective pressure. Most of the exposed surface is antigenically variable, so antibodies elicited against one strain lose affinity for the next.

- **Variable regions** — Most of the surface protein. Changes from one season and one strain to the next.
- **Conserved region** — A small part the pathogen cannot change without losing function. These epitopes of limited variability are our targets.

## A conventional vaccine presents the whole protein.

The response is immunodominated by the large variable surfaces. The conserved epitopes are largely ignored.

**Before the pathogen drifts** — Most antibodies target the variable regions, because those are the largest and most visible.

**After the pathogen drifts** — Most of that response no longer binds. The vaccine must be reformulated, and remains one step behind the pathogen. One antibody still fits: the one raised against the conserved region.

## nCage inverts this.

Three steps, in order. The pathogen itself is never needed.

### 01 Take the conserved epitope

We isolate the conserved epitope alone, defined by its three-dimensional structure rather than by the protein around it.

### 02 Design a protein scaffold from scratch

We then design a de novo protein scaffold: a new protein, built to hold the epitope in the conformation it adopts on the native antigen.

### 03 Mount the epitope on the scaffold

The epitope is grafted onto the scaffold and constrained in its native shape. The product is a synthetic antigen.

### Synthetic antigen

- Epitope held in its natural shape
- No variable surface to distract the immune system
- Designed and made without the pathogen

## Displayed at the size and shape of a virus

The synthetic antigens are then displayed on the TRAP-cage: a programmable protein nanoparticle that self-assembles from identical subunits.

### Multivalent display

Synthetic antigens mount on the outside of the cage in a regular geometric array, at the dimensions of the virion — the pattern B cells recognize most efficiently.

### Cargo in the lumen

The cage interior can also carry cargo: for example a conserved internal antigen, to drive a T cell response alongside the antibody response.

### A focused response

The result is a strong antibody response directed at the conserved epitope, and nothing else.

_Figure: The TRAP-cage itself: rings of eleven TRAP subunits, joined at their vertices by gold(I) ions, as resolved by cryo-electron microscopy._

## The pathogen can vary. The vaccine does not have to.

Because the epitope is conserved, the antibodies raised against it retain binding across circulating strains — and across variants that have not yet emerged.

**10× higher antibody titre** than the same antigen given alone, in soluble form, in preclinical models.

The pathogen varies. The antigen does not.

## Two design decisions, one platform

- **Epitopes of limited variability** — Conserved, structurally constrained targets, isolated from the pathogen and defined by their three-dimensional shape.
- **De novo scaffolds and multivalent display** — Epitopes held in their native conformation on designed protein scaffolds, and arrayed on the TRAP-cage at the dimensions of a virus.

nCage Therapeutics designs particles for next-generation vaccines.