Periodic Reporting for period 1 - BWAIN (Black Widow Antivenom Innovation Necessity)
Période du rapport: 2022-05-01 au 2023-10-31
Widow spiders are spread worldwide, and their bite induces severe envenomation symptoms that can lead to a complex syndrome known as latrodectism and death in severe cases. The only available specific treatment consists of polyclonal antibodies derived from horse plasma obtained by hyperimmunization with black widow spider venom. However, this process is slow, dangerous, and implies the continuous use of large domestic animals (mainly horses) in the manufacturing process. Venom unavailability is a significant supply chain bottleneck in antivenom manufacture, which imposes a very high product cost. Also, the efficacy of this horse-derived product suffers from batch-to-batch variation, resulting in variable efficacy profiles for different batches. Finally, the non-human nature of the horse-derived antibodies may provoke severe adverse immunological reactions. The high prevalence of adverse reactions severely limits its use, and antivenom use is thus reserved for only the most extreme cases, while not being administered at all to the many patients with asthma, atopy, or other allergy-related conditions.
In this project, we are developing a recombinant antivenom based on a single broadly-neutralizing fully human monoclonal antibody that can neutralize the toxic effects of widow spider bites. According to WHO nomenclature, this antibody will be called Latrotoxumab, and it will be safer to administer, more efficacious, as well as cost-competitive with existing antivenoms. In this ERC PoC project, which is based on results obtained in the ERC StG project MABSTER (grant number 850974), we will explore the commercial potential of Latrotoxumab and lay the first foundation for a spin-off company (Fang Pharma) by securing in vivo PoC, securing IPR, developing a regulatory, manufacturing, and clinical trial plan, and preparing a fully-flexed business plan, incl. market, pricing, and SWOT analyses, identification of business growth opportunities (partners and investors), and exit strategy.
Beyond Latrotoxumab, the this proof-of-concept project, and the establishment of Fang Pharma, is paving the way for developing and commercializing other recombinant antivenoms for other life-threatening venomous animals like funnel-web spiders, recluse spiders, or even scorpions and snakes.
In this project, we are developing a recombinant antivenom based on a single broadly-neutralizing fully human monoclonal antibody that can neutralize the toxic effects of widow spider bites. According to WHO nomenclature, this antibody will be called Latrotoxumab, and it will be safer to administer, more efficacious, as well as cost-competitive with existing antivenoms. In this ERC PoC project, which is based on results obtained in the ERC StG project MABSTER (grant number 850974), we will explore the commercial potential of Latrotoxumab and lay the first foundation for a spin-off company (Fang Pharma) by securing in vivo PoC, securing IPR, developing a regulatory, manufacturing, and clinical trial plan, and preparing a fully-flexed business plan, incl. market, pricing, and SWOT analyses, identification of business growth opportunities (partners and investors), and exit strategy.
Beyond Latrotoxumab, the this proof-of-concept project, and the establishment of Fang Pharma, is paving the way for developing and commercializing other recombinant antivenoms for other life-threatening venomous animals like funnel-web spiders, recluse spiders, or even scorpions and snakes.
During the project, we successfully screened an array of several IgG binders against alpha-Latrotoxin, identifying the most affine binders for functional characterization in ex-vivo and in-vivo assays. Despite having seen initial good results (low Kd and ability to cross-react with desired targets), the selected top binders did not show in vivo neutralisation, forcing us to discontinue the planned maturation of the selected top candidates.
Following these learnings, we have documented both alpha-latrotoxin and latrodectins as promising targets for achieving potentially universal neutralization of widow spiders, covering venom from multiple species, due to the conserved nature of both alpha-latrotoxin and latrodectins. Thus, the way forward will be to initiate new discovery campaigns of targets, also including the option of evaluating the in-house single domain antibody libraries for potential binders, and restart the pre-clinical evaluation employing the established partner setup from the BWAIN project.
Following these learnings, we have documented both alpha-latrotoxin and latrodectins as promising targets for achieving potentially universal neutralization of widow spiders, covering venom from multiple species, due to the conserved nature of both alpha-latrotoxin and latrodectins. Thus, the way forward will be to initiate new discovery campaigns of targets, also including the option of evaluating the in-house single domain antibody libraries for potential binders, and restart the pre-clinical evaluation employing the established partner setup from the BWAIN project.
Overall, the BWAIN project has succeeded in carrying out all of the work packages described in the original application. The team has successfully achieved the following:
- Defined IPR strategy, with inspiration from other mAbs produced and patented from the lab (WP2)
- Developed a mature business plan with input from US experts, including a scoping of the regulatory framework under the Orphan Drug designation (WP4, 5)
- Carried out ex vivo and in vivo assays characterizing the antibody candidates (WP1)
- Established a stable CHO cell line for production of Latrotoxumab together with National Biologics Facility (WP3)
Despite reaching many of the goals for the project, especially revolving around the planned commercialisation of Latrotoxumab, the pre-clinical studies reported that none of the selected IgG or Fab candidates were capable of neutralizing black widow spider venom in vivo. Having still identified and validated two proper targets for a future broadly neutralizing widow antivenom (Latrodectin and alpha-Latrotoxin), the way forward will be to generate new binders and use the pre-clinical partner setup from the BWAIN project to validate new leads.
The team is currently evaluating the potential of inlicensing other candidates based on the work from the MABSTER project and initiate the spin-out process of Fang Pharma, as the learnings from the business plan and regulatory scoping could easily be implemented to other antivenoms. We remain confident that the BWAIN project has laid the foundation for commercialisation of recombinant antivenom technologies, despite the technical challenges faced during the project.
- Defined IPR strategy, with inspiration from other mAbs produced and patented from the lab (WP2)
- Developed a mature business plan with input from US experts, including a scoping of the regulatory framework under the Orphan Drug designation (WP4, 5)
- Carried out ex vivo and in vivo assays characterizing the antibody candidates (WP1)
- Established a stable CHO cell line for production of Latrotoxumab together with National Biologics Facility (WP3)
Despite reaching many of the goals for the project, especially revolving around the planned commercialisation of Latrotoxumab, the pre-clinical studies reported that none of the selected IgG or Fab candidates were capable of neutralizing black widow spider venom in vivo. Having still identified and validated two proper targets for a future broadly neutralizing widow antivenom (Latrodectin and alpha-Latrotoxin), the way forward will be to generate new binders and use the pre-clinical partner setup from the BWAIN project to validate new leads.
The team is currently evaluating the potential of inlicensing other candidates based on the work from the MABSTER project and initiate the spin-out process of Fang Pharma, as the learnings from the business plan and regulatory scoping could easily be implemented to other antivenoms. We remain confident that the BWAIN project has laid the foundation for commercialisation of recombinant antivenom technologies, despite the technical challenges faced during the project.