Overcoming Conservative Bias: Why Synthetic VHH Antibodies are the Future of Antibody Discovery

The biotech and pharma industies thrive on a balance of caution and innovation, carefully managing risks, while pushing the boundaries. In VHH antibody discovery, traditional llama immunization-derived VHHs have been the trusted standard over synthetic approaches since the 1990s. Isogenica’s synthetic VHH antibodies open new possibilities, providing a faster, more scalable, and legally secure solution for both complex and routine targets.

When many decision-makers across the industry prefer to stick to what they know, we identify the growing risks to the immunization-for-discovery process and ask where the line is between due caution and unscientific bias? 

The Biotech Industry’s Bias Toward Llama-Derived VHH Antibodies

VHH antibodies are single-domain antibody fragments comprised of the variable domain from heavy chain only antibodies – a type of camelid antibody found in llamas, alpacas, and similar species, which is responsible for antigen binding. VHH antibodies are 10 times smaller than conventional antibodies, characterized by high stability, facilitating their use as building blocks for larger therapies, as well as topical delivery, and long product shelf-life. Due to their unique characteristics, VHH antibodies have found applications in a variety of therapeutic areas, including antibody-drug conjugates, cell and gene therapies, bi-specifics, and molecular imaging.

For decades, the biotech industry has leaned towards animal-based antibody discovery, usually immunizing llamas and alpacas to find new antibodies, due to their long history and established success. However, this traditional approach to discovery and production of llama-derived antibodies comes with increasing limitations. In these situations, synthetic VHH antibodies present a powerful alternative, especially when targeting challenging antigens, or where highly precise targeting of a particular site on the antigen is required.

The Traditional Immunization Approach: Strengths and Hidden Risks

Llama-derived VHH antibodies have a strong proven track record. Researchers trust the traditional immunization method due to its familiarity in academic literature and longstanding history of industry adoption. However, the use of immunization-derived VHH antibodies also has drawbacks, including:

• Limited scale for expensive targets: Llamas and alpacas are large animals, so immunizing them requires large antigen quantities, which is a major challenge when developing antibodies for unstable or costly targets.

• Humanization risks: Llama-derived VHHs must be engineered for human use, often leading to loss of binding affinity or developability.

• Ethical & logistical issues: Llama immunisation involves unpredictable biological variability and concerns about animal welfare. When death of an animal occurs, it means restarting the clock on a discovery campaign.

• Intellectual property (IP) constraints: Many antibodies are developed against a relatively small group of “favorite” target antigens – but vast quantities of immune-derived antibodies against these targets have already been patented. Even across different animals, researchers are now pulling out less and less diverse sequences.

• Future Legislation Risks: In 2020, the EU faced a challenge to ban animal use in antibody research. LERU deemed a ban “premature” but urged scientists to prioritise using non-animal-derived antibodies and explore developing alternatives. (Read more about this topic here)

Considering these drawbacks, immunization-based discovery is not the best fit for every use case. Synthetic VHH antibody alternatives offer unique advantages for both difficult and easy targets.

Niche Opportunities Where Synthetic Discovery Has The Edge

Solving Difficult Targets

Some targets, such as complex, poorly immunogenic, or intracellular targets, pose significant challenge for animal immune systems, making them difficult to recognize or to genuinely represent the correct biological conformation when injected into tissues.

Isogenica’s synthetic VHH antibodies can solve these challenges in several ways:

• Library optimisation for tough targets: Unlike traditional methods, Isogenica’s pre-humanized synthetic libraries have been engineered for high-affinity binding, facilitating their binding to even to hard-to-reach epitopes.

• Scalability without antigen constraints: The development of synthetic VHH antibodies relies on high-throughput synthetic screening and does not require large antigen quantities. Thus, it is particularly suitable for scarce or expensive targets.

• Successful applications: Isogenica’s synthetic VHH antibodies have found successful applications in various fields, including oncology, intracellular and peptide targets, and conserved viral epitopes.

• Faster time-to-market: The traditional approach for antibody discovery and production is time consuming and labor intensive, with animal immunisation alone taking <8 months. Using a synthetic approach, companies can proceed through antibody discovery up to 3x faster.

If you are working to ambitious timelines or struggling to generate successful hits using llama-based methods, Isogenica’s synthetic approach may unlock new opportunities for successful antibody discovery and production. 

Addressing Intellectual Property Risks for Familiar Targets 

When it comes to targets, much of the “low-hanging fruit” has already been widely explored using traditional immunization methods. This means that biotech companies face higher risks of running into FTO or patentability issues when employing animal-derived antibodies. 

Isogenica’s synthetic VHH antibodies can minimise the risks of IP conflicts due to their unique characteristics: 

• Fully synthetic sequences: Isogenica’s libraries are inspired by llama sequences, but not directly derived from any biological material. As well as being entirely Nagoya Protocol compliant, our antibodies are distinct from immune-derived sequences. 

• Avoiding Immunization Bias: Synthetic antibodies are generated independently of an immune response – this means the sequences you pull out are not biased by the immune reactivity of particular regions on your target. 

• Pre-optimized frameworks for faster development: Isogenica’s library frameworks are designed to minimize or eliminate sequence liabilities, or even provide pre-humanized sequences using our huLlamdA® and VHHantage™ libraries. This means that time-consuming downstream lead engineering (often itself encumbered by methods patents) is minimal – getting you to preclinical studies faster.

If your target has significant existing patents or other prior art, Isogenica’s synthetic approach provides a streamlined, FTO-friendly solution. 

Faster, Smarter, and More Scalable Discovery 

Biotech companies working in the fields of oncology, immunology, and diagnostics face major challenges in the process of antibody discovery and development. The use of synthetic VHH antibodies gives biotech companies the ability to: 

• discover antibodies against hard-to-hit targets 
• avoid patent roadblocks in crowded fields 
• accelerate development timelines 
• reduce reliance on animals for discovery 

In many cases, using synthetic VHHs antibodies can be the key to turning potential into success. 

Isogenica’s synthetic VHH antibodies provide a faster, more reliable, and IP-friendly alternative, helping biotech companies achieve breakthroughs in areas where traditional methods are falling short. 

Solve Your Antibody Discovery Challenges with Isogenica 

All stages of antibody discovery and production may be associated with challenges. Isogenica is an innovative leader in the antibody discovery services space, and its vast synthetic VHH antibody libraries offer solutions for both difficult and familiar targets. Our expert team thrive on unusual projects, with scientists following each discovery project from start to finish as an extension of your own R&D team.  

Learn more about how Isogenica’s synthetic VHH antibodies perform.

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