Discover the power of VHHs for faster antibody discovery and development
Isogenica specialises in VHHs – single-domain antibodies that offer exceptional robustness, flexibility, and scalability across varied therapeutic and diagnostic applications such as ADC, bi-specifics, cell therapies and much more.
What are VHH antibodies?
VHHs are the smallest known, naturally occurring, antigen binding antibody fragment. In practice, this means they are a lot like full-length antibodies but smaller, simpler, and more robust.
Originally isolated from camelid species in the 1990s, these proteins represent the antigen binding region (VH domain) of a Heavy chain-only antibody.
VHH antibodies are often called by other names, but as proteins they all have identical origins and structure. VHHs are also known interchangeably as:
- nanobodies (trademarked as Nanobodies® by Ablynx in 2003)
- heavy-chain single domains
- single domain antibodies, or sdAbs
- heavy chain only variable domains
These early drugs were discovered using llama immunisations, but at Isogenica we mine the largest, most diverse synthetic VHH libraries on the market for pre-humanised leads using well-characterised, pre-defined frameworks.
The difference between VH and VHH antibodies
All antibodies have variable (V) regions, which is where the antigen binding function comes from. The part of the antibody that directly comes into contact with the antigen is known as the “paratope”.
In traditional Y-shaped antibodies, including human antibodies, the paratope is usually made up of two halves – one from the heavy (H) chain and one from the light (L) chain. A VH antibody is the half of this variable region paratope that comes from the heavy chain.
As the name suggests, heavy chain only antibodies lack a light chain. This means that all their antigen-binding activity is concentrated into just one place – the VHH domain.
The other important difference between VH and VHH antibodies is in their biochemistry. Because VH domains need to pair with a VL variable light chain domain to build their paratope, they have a “sticky” hydrophobic patch. The role of this hydrophobic surface is to stick to a similar surface on the VL domain, keeping the paratope stable.
However, when you try to express just one of these domains by itself, they can be prone to aggregation or mispairing. This can cause manufacturing or safety issues during drug development, and needs to be screened for carefully.
VHH Features
At around 10% of the size of a traditional monoclonal antibody, VHHs display the same highly sensitive and specific binding. Because all this binding is concentrated into a single protein unit, they are very simple proteins – easy to make rapidly from microbial or mammalian systems.
Unlike full-length antibodies, they do not naturally form pairs and prefer to exist in a monomeric, soluble form – ideal for therapeutics manufacture.
They are also not associated with complex immune modulatory functions which some full IgG therapies suffer from.
The big reason that Isogenica sees VHHs as special is their versatility. Because of their simplicity, they can easily link to other biomolecules, including other VHHs, for numerous applications.
With a decade of synthetic VHH discovery experience, Isogenica is building on this expertise to develop internal drug assets for oncology. To explore the many different therapeutic and diagnostic uses for VHHs, including Isogenica’s multi-specifics pipeline, check out our applications pages, and for answers to FAQs on VHHs.
VHH in the clinic
VHH single domains are one of the most accepted next generation antibody therapeutic formats.
Cablivi (caplacizumab) was the first FDA-approved single domain antibody therapeutic in 2019.
So far, VHH are being developed as:
- Monomers
- Bi-specifics
- Half-life extended
- CAR formats
| Drug | Sponsor | Domain Properties | Target | Indication | Status |
| Caplacizumab | Sanofi (Ablynx) | VHH | vWF | aTTP | Approved |
| LCAR-B38M | Legend/Janssen | Bi-paratopic VHH CAR-T | BCMA | Multiple Myeloma | Approved |
| Ozoralizumab | Taisho (Ablynx) | VHH | TNF | RA | Approved |
Envafolimab | Jiangsu Simcere Parmaceutical | VHH-Fc | PD-L1 | Cancer immunotherapy | Approved |
| Gefurulimab | Alexion | VHH | C5 | Myasthenia | Phase III |
| M1095 | Moonlake Immun | VHH Bi-specific | IL-17A IL-17F | Psoriasis | Phase IIb |
| BI836880 | Boehringer Ingelheim (Ablynx) | VHH Bi-specific | VEGF, Ang2 | NSCLC | Phase II |
| HPN328 | Harpoon | VHH-scFc Tri-specific | DLL3 | SCLC | Phase II |
Extending half-lives of VHH antibodies
Because VHHs are small, they can be cleared quickly from the bloodstream. This can be a useful feature for some applications, but often a longer plasma half-life is desirable.
Our VHH-based ISOXTEND® technology protects VHH biotherapeutics from kidney clearance by ‘piggybacking’ onto the serum albumin endocytic recycling pathway, significantly extending therapeutic half-life.
Explore the science behind our antibody discovery platforms
White Paper “Data-Driven Validation of Synthetic VHHs”
This white paper provides a data-driven validation of Isogenica’s synthetic VHH libraries, powered by Colibra® technology. Designed for biotech and pharmaceutical scientists, it demonstrates how these libraries enhance and accelerate drug discovery, particularly in oncology and immunotherapy. DownloadExtending half-lives of VHH antibodies
Because VHHs are small, they can be cleared quickly from the bloodstream. This can be a useful feature for some applications, but often a longer plasma half-life is desirable. DOWNLOADAdvantages of VHH in bi-specifics
To learn more about the application of VHHs in bi-specifics, we have condensed our expertise into a downloadable Application Note. DOWNLOADOptimizing CAR-T and T-cell antibody engagers: a role for VHH single domain antibodies
This whitepaper summarises the clinical and research landscape for CAR-T and T-cell engaging antibody therapies and show how single domain VHH antibodies can be applied to optimise the next generation of these important new therapeutic modalities. DOWNLOADIsogenica’s PD-L1 VHH as Functional Antagonists
PD-1 is an immune checkpoint protein expressed on the surface of multiple types of immune cells, including antigen-stimulated T-cells and tumour specific T-cells1. Interaction between PD-1 and its ligands (PD-L1 or PD-L2), is responsible for the regulation of T-cell activation, apoptosis, proliferation and cytokine production. DOWNLOADAnti-LRP5/6 VHH inhibits WNT pathway and prevents tumour growth
VHH are the variable domain of heavy chain only antibodies. They are small in size (~15 kD) and biophysically robust. With tunable half-lives, these antibodies are ideal for targeting inaccessible epitopes, achieving enhanced tissue penetration, multi-target binding and formatting for payload delivery… DOWNLOAD