Synthetic VHH Libraries
Isogenica’s VHH libraries are based on decades of research into synthetic biology and display technologies. We are always learning, improving, and testing our libraries. Our current best-performing libraries are:
Mid-diversity library combining human frameworks with rationally designed, fully human CDRs. Pre-screened sequences with almost zero CMC liabilities.
Ultra-high diversity CDRs based on original llama frameworks. Equivalent to the circulating immune repertoire of 1 million llamas and built using Colibra(TM) technology for reduced CMC liabilities.
The same ultra-high diversity, low-risk CDRs based on human frameworks for even lower immunogenicity.
When talking about synthetic DNA libraries, size matters. However, the larger the library, the harder it gets to display.
Once any library is moved into a biological system like E. coli, sampling more than 109– 1010 different sequences becomes extremely challenging.
Even CIS display – Isogenica’s proprietary cell-free display system – is limited to a sample size of ～1012, although this is still up to 1000x bigger.
How do synthetic libraries compare with immune libraries?
Due to the in vivo phenomenon of somatic hypermutation, it is easier to generate VHHs with extremely high affinities (picomolar range) from animal immunisations. Typically, leads from Isogenica’s synthetic libraries have low nanomolar affinities, which are optimal for drug development.
But what about the process?
Immunisation of a large animal such as a llama or alpaca takes a lot of target antigen, and a long time. A good immune library can only be made after several months of waiting, boosting, and titre checking, and can take up to 8 months. In contrast, synthetic libraries can be mined immediately.
Furthermore, llama-derived hits require humanisation and may contain high-risk CMC liabilities such as extra cysteine residues or glycoslation sites. Isogenica’s libraries are built using methods designed to reduce the frequency of these liabilities and reduce the downstream engineering work required to turn immune-derived VHHs into potential drugs.
Purely in vitro, Isogenica’s proprietary single-domain libraries enable speed and efficiency unmatched by animal immunisation.