Description

Here we shine a spotlight on one of 2025's most relevant ncAA-driven innovations; a "new-to-nature" superpower that could rewrite how we build bispecific antibodies. Forget DNA fusion tricks — these scientists stitch proteins together exactly where they want!

In a standout preprint from Roman Adomanis et al., Blaise Kimmel Lab, The Ohio State University, researchers used genetically encoded non‑canonical amino acids (ncAAs) to craft modular bispecific nanobodies with fully controlled topology — something conventional protein expression could never achieve. These amino acids don't exist in nature, but once woven into nanobodies, they become perfect chemical anchoring points. As a result: geometry becomes a design variable, potency can be tuned without re-cloning DNA and assembly is fully homogeneous and CMC‑friendly.

Citation: Adomanis et al., 2025

Bispecific antibodies engage two targets simultaneously, but conventional approaches (DNA fusions, knobs-into-holes) constrain geometry and complicate manufacturing. Non-canonical amino acids offer a modular alternative: each domain is expressed separately with an ncAA at a defined site, then assembled via click chemistry with full control over topology.

Using genetically encoded azidolysine (AzK) in nanobodies, researchers created bispecific constructs where the orientation and spacing between domains was a tuneable design parameter. Unlike genetic fusions, which lock in a single geometry at the DNA level, ncAA-mediated assembly allows the same domains to be connected in different configurations without re-cloning. The resulting constructs were homogeneous and manufacturing-friendly (Adomanis et al., 2025).

This modular approach reduces development timelines: once individual domains are validated, new bispecific combinations can be assembled chemically rather than requiring new expression constructs. It applies to nanobodies, single-chain antibodies, and other scaffold proteins.

Source publication