Before the pathogen drifts
Most antibodies target the variable regions, because those are the largest and most visible.
Technology
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.
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Synthetic antigens, in two and a half minutes
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2 min 35 s
Synthetic Antigen Design
The idea
The pathogen varies. The antigen does not. That is how a synthetic antigen outruns antigenic variation.
Chapter 01 — A pathogen changes its surface
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.
Chapter 02 — The immune system responds mainly to what changes
A conventional vaccine presents the whole protein.
The response is immunodominated by the large variable surfaces. The conserved epitopes are largely ignored.
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.
Chapter 03 — nCage keeps only the part that does not change
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
Chapter 04 — Dozens of copies on a TRAP-cage
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.
01
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.
02
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.
03
A focused response
The result is a strong antibody response directed at the conserved epitope, and nothing else.
Chapter 05 — Antibodies that fit every variant
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.
Strain A
Strain B
Next season
The pathogen varies. The antigen does not.
Synthetic antigens, by design
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.