Learn how VHHs can revolutionize CAR-T cell therapy
Small, stable and robust, VHH antibiodies – often called nanobodies – offer an attractive solution as targeting agents in cell therapies.
Explore the benefits of VHHs in CAR-T cell therapy and learn how this innovative approach can enhance the effectiveness of next-generation cancer treatments.
Scientific & Therapeutic Context
About Cell Therapy
Since the first anti-CD19 CAR-T cell therapy was approved in 2017, there’s been an explosion of interest in using engineered immune cells to treat cancer. CAR constructs consist of an external antibody-based targeting domain – typically an scFv antibody fragment consisting of heavy and light chains – together with a transmembrane domain and increasingly complex intracellular costimulatory domains.
More recently, we’ve seen the emergence of tandem CARs (TanCARs) with bi- or tri-specific antibody recognition domains, which increase specificity and reduce the likelihood of antigen escape.
However, the move towards the creation of more sophisticated CARs, both inside and outside the cell, is hitting the limits of what can be achieved with scFv targeting domains.
This shift from scFvs to newer, smaller modalities is exemplified by the recent clinical success and FDA approval of CARVYKTI™, a VHH-based anti-BCMA CAR-T therapy with bi-paratopic binding domains originally isolated from llamas. But we can go further still.
Our synthetic, humanised single chain VHH antibodies are a neat solution to the challenges of engineering next-generation cell therapies. Here’s why.
Advantages of
VHH antibodies in CAR-T:
Smaller constructs mean more space for multi-specific targeting modules or next-generation signalling domains.
References:
1. Jayaraman J et al. (2020) Ebiomedicine 58: 102931
2. Lamers CH, et al. (2011) Blood 117(1):72-82
3. Ackaert C et al. (2021) Front. Immunol. 12: 632687
4. Desmyter A et al. (1996) Nat Struct Biol 3(9): 803-811
Key advantages of small format VHH antibodies
Isogenica’s three libraries of small format VHH antibodies are a neat solution to both problems.
Derived from camelids, VHHs are half the size of conventional scFv fragments and composed of a single, highly soluble, variable domain.
Unlike heavy or light chains from an scFv, the innate desire to pair with another chain is absent in these molecules due to preservation of key ‘hallmark’ residues that define VHH antibodies as a class, reducing the chance of ectodomain aggregation.
Unlike conventional mouse-derived monoclonal antibodies, even animal-derived VHHs are regarded to have low immunogenicity. In addition, Isogenica’s VHH antibodies are also available in humanised variants, making it possible to identify low-immunogenicity leads without the need for lengthy immunisation protocols or extensive protein engineering.
Check out our curated VHH resources
Check out our curated VHH resources to learn more about the advantages of this exciting modality in your CARs and get in touch for a chat with our experts to discover how we can help you with your ectodomain engineering challenges.
Interested in exploring VHHs for cell therapy? Let’s talk.
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