EgA1 is a camelid-derived VHH that recognises a challenging epitope near the interface of EGFR domains II and III.

EgA1 provides a structural and functional example of how VHHs can target challenging epitopes on cancer-relevant receptors.

Target:

Epidermal growth factor receptor (EGFR)

Why it matters:

EGFR is a receptor tyrosine kinase involved in regulating cell growth, proliferation and survival. Abnormal EGFR signalling is implicated in several cancers, making it an important therapeutic target.

EGFR activation involves ligand-induced conformational changes that enable receptor dimerisation and downstream signalling.

While EGFR is already a well-established therapeutic target, not all potentially useful binding sites are equally accessible to conventional antibodies. Some epitopes are in structurally constrained regions of the receptor, creating opportunities for alternative binding approaches.

EgA1 is a camelid-derived VHH that recognises a challenging epitope near the interface of EGFR domains II and III, demonstrating how VHHs can access functionally important regions of well-studied therapeutic targets.

What makes it special:

• Accessing a difficult-to-reach epitope: EgA1 binds to a structurally constrained region of EGFR. Structural studies illustrate how its compact antigen-binding surface can engage an epitope that is difficult for conventional antibody binding surfaces to access.
• Interfering with receptor activation: EgA1 inhibits EGFR activation by interfering with the conformational changes associated with receptor activation and dimerisation.
• A different approach to a familiar target: EgA1 demonstrates how VHHs can recognise alternative epitopes on a therapeutically relevant receptor, potentially expanding the range of approaches available for modulating receptor function.

Big impact:

EgA1 provides a structural and functional example of how VHHs can target challenging epitopes on cancer-relevant receptors.

Its significance lies in demonstrating that VHH binding geometry can provide access to functionally important receptor surfaces that may be difficult for conventional antibody formats to engage.

This illustrates the potential of VHHs to expand the range of epitopes and mechanisms available.

Cool fact:

• EgA1 and another EGFR-targeting VHH, 9G8, recognise a related region of EGFR through different binding orientations.
• Their structures highlight how VHHs can engage constrained receptor surfaces in distinct ways, revealing alternative opportunities to interfere with the activity of a well-characterised therapeutic.

Reference

Schmitz KR et al. Structural Evaluation of EGFR Inhibition Mechanisms for Nanobodies/VHHs. Structure. 2013; 21, 1214-1224. doi:10.1016/j.str.2013.05.008

Schmitz et al. EgA1and cetuximab antibody chains with the extracellular domain of EGFR. 2013; PDB ID: 4KRO. Image adapted from RCSB PDB (RCSB.org).