VHH Nanobodies
Constructive.bio enhances VHH nanobodies through site-specific ncAA incorporation for half-life extension, payload conjugation, and multispecific formatting — all produced via scalable fermentation. Our platform addresses the two fundamental limitations of nanobodies (rapid renal clearance and limited chemical handles for functionalisation) without the need for Fc fusion or genetic format engineering.
The Problem
VHH nanobodies (~15 kDa) offer superior tissue penetration and tumour infiltration compared to conventional antibodies, but their small size causes rapid renal clearance (half-life ~1.5 hours). Current solutions — Fc fusion, albumin-binding domains, or random PEGylation — add molecular bulk that negates the size advantage, introduce heterogeneity, or require complex genetic engineering. The lack of accessible, site-specific chemical handles also limits payload conjugation for nanobody-drug conjugates.
Our Approach
Constructive.bio incorporates ncAAs at defined framework positions distant from CDR loops to preserve binding affinity. Azide-bearing ncAAs enable site-specific PEGylation for controlled half-life extension (targeting 24–72 hours) without Fc fusion. The same or additional ncAA positions provide orthogonal click chemistry handles for payload conjugation, dye labelling, or bispecific formatting. All modifications are made during fermentation expression, not post-translational chemical steps.
Key Capabilities
Site-specific PEGylation extending half-life from ~1.5h to 24–72h without Fc fusion
Scalable fermentation production of modified nanobodies using standard bioreactor infrastructure
Orthogonal click chemistry handles for conjugation, labelling, or multispecific formatting
Modification at framework positions — CDR binding loops untouched