Leveraging Our Strengths to Combat SARS-CoV-2

Talem Therapeutics has been actively involved in COVID-19 research since January 2020. Monoclonal antibodies were derived from several animal species, including transgenic OmniRat® rodents, rabbits, human and llama, to access a broad epitope coverage. We exploit multiple in vivo and in vitro discovery platforms (B cell cloning, hybridoma, and phage display) and multiple antibody formats (IgG, scFv, and VHH) to increase the chances of finding clones with unique/rare epitopes and facilitate their reformulation into bispecifics or other modular formats. Our multinational teams in North America and Europe have developed a rich SARS-CoV-2 antibody portfolio with deep epitope and functional diversity.

The Polytope™ Advantage

  • Leverages the complementary strengths of multiple antibody discovery platforms to cover blind-spots inherent to each method and generate diversified panels of antibody candidates
  • Broad epitope coverage allows for the rational curation of multi-antibody cocktails to protect against mutational escape as SARS-CoV-2 evolves
  • Antibody cocktails provide opportunities for unlocking synergistic effects to boost protection by engaging multiple mechanisms of action in concert and may allow for lower dosing regimens than for monotherapies
  • Provides the foundation of our COVID-19 therapy and a reservoir of back-up molecules to enable plug-and-play reformulations to address emerging variants of concern and seasonal strains of the SARS-CoV-2 virus
  • Platform suitable for other emerging pathogens

Notable Strengths of Each Platform

Species & Format:

  • Fully human antibodies derived from humans and transgenic OmniRat® rodents require minimal engineering to make them clinically ready.
  • Llama-based VHH’s are facile to humanize given their similarity to human sequences. The VHH format is uniquely suited to probe epitope canyons within a target’s structure
  • Rabbits are known for their ability to produce high affinity antibodies targeting a broader range of epitopes than is possible by rodents, allowing access to rare or mechanistically differentiated epitopes that may not be produced by rodents
  • Different species have their own biases in how they recognize 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 complementary use of different antibody generation methods (in vivo and in vitro) overcomes any inherent biases in the antibody repertoires produced from each method, 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 human library 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, as soon as recombinant or cell-associated targets are available for use as panning reagents.

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 updated and optimized in response to emerging disease variants, improving durability of our SARS-CoV-2 therapies and enabling expanded use for novel, emerging, infectious diseases.

Current status: We are presently in discussions with CDMOs regarding cGMP, clinical manufacturing while concurrently preparing for safety and toxicology studies to support an IND application.
Please contact bd@talemtherapeutics.com, with scientific questions regarding our PolyTope™ Advantage.