Species & Format:

• Fully human antibodies derived from humans and transgenic OmniRat® rodents that require minimal engineering to make them clinically ready.
• Llama-based VHH’s are easy to humanize given their similarity to human sequences. The VHH format is uniquely suited to probe epitope canyons or deep clefts within a target’s structure (especially reported for pathogens) that are immunologically silent to standard IgG-based antibodies that generally access surface epitopes.
• Rabbits are known for their ability to produce high affinity antibodies targeting a broader range of epitopes than is possible by rodents, allowing to access rare or mechanistically differentiated epitopes that may not be produced by rodents.
• Different species have their own biases in how they see the target and produce an immune response.
• The monovalent scFv and VHH formats allow for their facile combination into bispecifics. In a modular way, they offer flexibility, combining specificities, but also in choosing different formats like full-length IgG or other Fc-fused formats (e.g., VHH-hFc etc.).

Discovery:

• The use of in vitro (phage display) and in vivo (hybridoma, B cell cloning) is another angle where we have a competitive advantage. Each antibody generation method introduces different biases into the produced antibody repertoires due to the way antibodies are generated, enriched, and identified. Hybridoma relies on an immune-challenge with an immunogen or a vaccination, which can make it slower than in vitro methods, but has the advantage of delivering highly specific, naturally affinity matured antibodies. The direct cloning and sequencing of B cells overcomes the inefficiency of hybridoma fusions and combines it with the natural pairing of the variable regions of the heavy and light chains.
• In vitro methods rely on panning/ enrichment with a target on an immune repertoire that is derived from naïve (unchallenged) individuals or immunized/ vaccinated/ diseased individuals. We use one naïve llama and two human libraries, one is naïve and sourced from healthy donors, the other sourced from autoimmune-diseased patients. An advantage of our in vitro libraries is that we can dip into them on demand to pan for antibodies against any antigen of choice.

Taken together, we use a rich diversity of methods and platforms to increase the chance of converging upon a collection of lead candidates which can be rapidly reformulated and reformatted. This allows for PolyTope™ therapies to be continuously improved in response to emerging disease variants, improving durability of our SARS-CoV-2 therapies and enabling expanded use for novel, emerging, infectious diseases.