VHHs: essential building blocks for next generation therapeutics

What is a VHH antibody?

Heavy chain antibodies are a unique type of single domain antibodies (sdAbs) found in camelids (camels, llamas, and alpacas). The antigen binding region (paratope) of heavy-chain antibodies is solely formed by a single variable domain called VHH or Nanobody®. The small size (15 kDa) and stable fold of VHH domains have led to the use of VHH domains in diagnostic and imaging studies. Moreover, they serve as crucial building blocks in a variety of pre-clinically and clinically investigated bivalent, multivalent, and multi-specific antibodies in therapeutic areas like oncology, autoimmunity, and infectious diseases.
Antibody Cartoon 1

Who Turned off the Light(chain)s?

Antibody Cartoon 2
Key differences in human and camelid VH domains  allow camelid VHH to act in the absence of a paired light chain. Among these differences are longer complementarity determining region H3 (CDR-H3) loops, substitutions in the framework 2 (FWR2) region, which is responsible for heavy–light chain pairing in conventional heavy chain (HC)/light chain (LC) antibodies, and non-canonical disulfide bonds. The FWR2 substitutions, also referred to as ‘hallmark residues’, consist of changes from hydrophobic to more hydrophilic residues, which  lead to a more soluble interface in the absence of the light chain.
The unique structural and biophysical properties of VHH further their utility and ability to translate to therapeutic applications. These advantages include: 
  • Thermostability
  • Solubility and Stability 
  • Long CDR3 and access to cryptic epitopes 
  • Low immunogenicity 
  • Enhanced tissue penetration

 

Therapeutic Applications

VHHs are being explored so extensively because of their ease of engineering and amenability to next generation therapeutics. Common applications of VHHs include:
  • Bispecifics 
  • Multispecifics 
  • Cell therapy
  • ADC and radiotherapies
  • Diagnostic imaging
Each therapeutic modality requires its own set of unique parameters. Abkyu offer contract research services for VHH discovery that are custom built for these specific therapeutic applications. 
 

Clinical Successes of VHH antibodies

Despite only being discovered about 25 years ago, VHHs have garnered increasing attention due to their unique properties such as smaller size, increased stability, and ease of production compared to traditional antibodies. Several VHH-based drugs have reached clinical approval, primarily in oncology and immunology including:
  • Envafolimab
  • Coltacabtegene autoleucel
  • Caplacizumab
  • Ozoralizumab
The field is still expanding, with many VHH-based drugs in various stages of clinical trials. The success of these therapies indicates that we are likely to see even more VHH-based biologic drugs approved in the future.

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References

Mullin, M., McClory, J., Haynes, W., Grace, J., Robertson, N., & van Heeke, G. (2024). Applications and challenges in designing VHH-based bispecific antibodies: Leveraging machine learning solutions. Journal of Antibody Technology and Engineering, Volume 12, pp. 34-56.

Asaadi, Y., Fazlollahi Jouneghani, F., Janani, S., & Rahbarizadeh, F. (2021). A comprehensive comparison between camelid nanobodies and single chain variable fragments. Biomarker Research, 9, Article 87. https://doi.org/10.1186/s40364-021-00323-w

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