Periodic Reporting for period 1 - iPYRO (Custom-Made Designer Macrophages to Revolutionize the Safety of Parenteral Drugs)
Período documentado: 2023-01-01 hasta 2024-06-30
Ensuring the safety of parenteral drugs is essential due to their substantial socioeconomic impact. The iPYRO proposal introduces a groundbreaking method for the scalable production of human macrophages, offering a highly standardized, cost-effective, "off-the-shelf" macrophage-based cell product with the potential to revolutionize parenteral drug safety. According to the European Pharmacopoeia (Ph. Eur.), all parenteral drugs—including injections, infusions, medical devices, and advanced therapy medicinal products (ATMPs)—must undergo regular pyrogen testing to verify their purity and safety. Pyrogens, substances capable of inducing adverse febrile or even lethal reactions, can originate from bacteria, viruses, fungi, or other sources.
Currently, parenteral drug safety is primarily assessed using the Rabbit Pyrogen Test (RPT) or the Limulus Amebocyte Lysate (LAL) assay, both of which rely on animals and fail to accurately reflect human physiology. Over 25 years ago, the Monocyte Activation Test (MAT) was introduced as a more physiologically relevant alternative, but it uses non-standardized peripheral blood mononuclear cells (PBMCs) from undefined human donors or artificial, cancer-derived monocytic cell lines. These sources present significant limitations, such as the lack of suitable donors, non-standardized PBMCs, risk of infectious contamination, and considerable donor-to-donor variability.
The iPYRO proposal addresses these challenges by harnessing human induced pluripotent stem cells (iPSCs) to create a fully standardized monocyte/macrophage (iMonoMac) cell product. This innovative product offers unparalleled quality and MAT-specific functions. Derived from fully characterized iPSCs, the iMonoMac cells can be produced using a scalable, industry-compatible differentiation platform, eliminating the need for donor reliance and reducing variability. Unlike previous methods that required multiple donors, the iMonoMac cell product can be generated on demand using highly efficient, scalable differentiation systems, enabling a fully controlled and sterile manufacturing process that is free from batch-to-batch variations and animal-derived components.
Currently, parenteral drug safety is primarily assessed using the Rabbit Pyrogen Test (RPT) or the Limulus Amebocyte Lysate (LAL) assay, both of which rely on animals and fail to accurately reflect human physiology. Over 25 years ago, the Monocyte Activation Test (MAT) was introduced as a more physiologically relevant alternative, but it uses non-standardized peripheral blood mononuclear cells (PBMCs) from undefined human donors or artificial, cancer-derived monocytic cell lines. These sources present significant limitations, such as the lack of suitable donors, non-standardized PBMCs, risk of infectious contamination, and considerable donor-to-donor variability.
The iPYRO proposal addresses these challenges by harnessing human induced pluripotent stem cells (iPSCs) to create a fully standardized monocyte/macrophage (iMonoMac) cell product. This innovative product offers unparalleled quality and MAT-specific functions. Derived from fully characterized iPSCs, the iMonoMac cells can be produced using a scalable, industry-compatible differentiation platform, eliminating the need for donor reliance and reducing variability. Unlike previous methods that required multiple donors, the iMonoMac cell product can be generated on demand using highly efficient, scalable differentiation systems, enabling a fully controlled and sterile manufacturing process that is free from batch-to-batch variations and animal-derived components.
The primary goal of the iPYRO project was to develop and position iMonoMac as a commercial cell product for use in the MAT assay. To achieve this, the project’s overall objectives were addressed through three key work packages (WP):
• WP 1: Regulatory Compliance and Validation
• WP 2: R&D and Business Development
• WP 3: Licensing Model and Commercial Strategy
WP 1: Regulatory Compliance and Validation
WP 1 focused on quality assurance and validation, critical steps in preparing iMonoMac for regulatory approval in the MAT assay and gaining customer confidence. To demonstrate the universal applicability of iMonoMac and its ability to capture donor-to-donor variability, we produced iMonoMac cells from over six donors of diverse ethnicities, genders, and ages in a standardized manner, beneficial for MAT applications.
We successfully validated iMonoMac cells from scalable bioreactor cultures, proving that large-scale production is feasible and supports continuous cell supply for the MAT. Additionally, we explored alternative differentiation cultures, avoiding the use of animal-derived materials such as Fetal Calf Serum or animal-produced cytokines and antibodies. This led to the development of a fully animal-free MAT assay, compliant with European Pharmacopoeia standards. Furthermore, we created an "off-the-shelf" cryopreserved iMonoMac cell product.
While we established a proof of concept, further work is required to meet full industry expectations. Most studies were conducted in a research environment, in alignment with regulatory bodies like the Paul Ehrlich Institute. We assembled a team of experts from academic, regulatory, and industry backgrounds to shape iMonoMac’s development. A portion of this work was published in the peer-reviewed journal Biofabrication (Abdin et al., 2024), where we tested parenteral drugs and demonstrated the assay's capabilities, including its effectiveness in detecting endotoxin contamination in pharmaceutical preparations.
WP 2: R&D and Business Development
WP 2 centered on research and development, streamlining the iMonoMac product for future commercialization through a spinout or licensing. This involved creating multiple iMonoMac cell products and assembling a dedicated team to drive the spinout and/or licensing efforts. In collaboration with the tech-transfer department of MHH, we brought together a project manager and a business developer whose expertise facilitated industry connections, attracted venture capital, and enabled participation in pitching and business events.
iPYRO gained significant visibility and recognition at various events, including the German SPRIND initiative. We earned accolades at pitching competitions such as the Institute of Biomedical Translation (IBT) (finalist) and Bionnale in Berlin (3rd place). Engagements with investors and industry stakeholders helped incorporate their feedback into product development, boosting awareness and interest in iMonoMac. These interactions culminated in the creation of a business plan, which has now been finalized and is being considered as a potential path for a spinout. However, due to strong industry interest, we are also exploring an out-licensing model with industrial partners.
WP 3: Licensing Model and Commercial Strategy
WP 3 focused on evaluating a suitable licensing model and identifying a commercial iPSC line for the spinout. Serving as a bridge between the laboratory work in WP 1 and commercialization efforts, WP 3 involved conducting a market research analysis for iMonoMac, targeting not only parenteral drugs but also emerging in vitro bioassays. An agency-facilitated contact list enabled interviews with industry stakeholders, leading to a highly successful market analysis that provided insights into additional markets and broadened connections beyond parenteral drugs.
A freedom-to-operate (FtO) analysis was performed to assess the necessary intellectual property (IP) for the anticipated spinout. This completed FtO analysis offered an updated overview of relevant knowledge and technologies associated with iPSCs and iPSC-derived macrophages.
• WP 1: Regulatory Compliance and Validation
• WP 2: R&D and Business Development
• WP 3: Licensing Model and Commercial Strategy
WP 1: Regulatory Compliance and Validation
WP 1 focused on quality assurance and validation, critical steps in preparing iMonoMac for regulatory approval in the MAT assay and gaining customer confidence. To demonstrate the universal applicability of iMonoMac and its ability to capture donor-to-donor variability, we produced iMonoMac cells from over six donors of diverse ethnicities, genders, and ages in a standardized manner, beneficial for MAT applications.
We successfully validated iMonoMac cells from scalable bioreactor cultures, proving that large-scale production is feasible and supports continuous cell supply for the MAT. Additionally, we explored alternative differentiation cultures, avoiding the use of animal-derived materials such as Fetal Calf Serum or animal-produced cytokines and antibodies. This led to the development of a fully animal-free MAT assay, compliant with European Pharmacopoeia standards. Furthermore, we created an "off-the-shelf" cryopreserved iMonoMac cell product.
While we established a proof of concept, further work is required to meet full industry expectations. Most studies were conducted in a research environment, in alignment with regulatory bodies like the Paul Ehrlich Institute. We assembled a team of experts from academic, regulatory, and industry backgrounds to shape iMonoMac’s development. A portion of this work was published in the peer-reviewed journal Biofabrication (Abdin et al., 2024), where we tested parenteral drugs and demonstrated the assay's capabilities, including its effectiveness in detecting endotoxin contamination in pharmaceutical preparations.
WP 2: R&D and Business Development
WP 2 centered on research and development, streamlining the iMonoMac product for future commercialization through a spinout or licensing. This involved creating multiple iMonoMac cell products and assembling a dedicated team to drive the spinout and/or licensing efforts. In collaboration with the tech-transfer department of MHH, we brought together a project manager and a business developer whose expertise facilitated industry connections, attracted venture capital, and enabled participation in pitching and business events.
iPYRO gained significant visibility and recognition at various events, including the German SPRIND initiative. We earned accolades at pitching competitions such as the Institute of Biomedical Translation (IBT) (finalist) and Bionnale in Berlin (3rd place). Engagements with investors and industry stakeholders helped incorporate their feedback into product development, boosting awareness and interest in iMonoMac. These interactions culminated in the creation of a business plan, which has now been finalized and is being considered as a potential path for a spinout. However, due to strong industry interest, we are also exploring an out-licensing model with industrial partners.
WP 3: Licensing Model and Commercial Strategy
WP 3 focused on evaluating a suitable licensing model and identifying a commercial iPSC line for the spinout. Serving as a bridge between the laboratory work in WP 1 and commercialization efforts, WP 3 involved conducting a market research analysis for iMonoMac, targeting not only parenteral drugs but also emerging in vitro bioassays. An agency-facilitated contact list enabled interviews with industry stakeholders, leading to a highly successful market analysis that provided insights into additional markets and broadened connections beyond parenteral drugs.
A freedom-to-operate (FtO) analysis was performed to assess the necessary intellectual property (IP) for the anticipated spinout. This completed FtO analysis offered an updated overview of relevant knowledge and technologies associated with iPSCs and iPSC-derived macrophages.
In summary, the efforts undertaken within iPYRO have significantly advanced the iMonoMac product towards market readiness. In particular, the intensified discussions with both investors and industry stakeholders have been instrumental in driving the product’s development forward. Additionally, expanding the team has provided valuable perspectives for evaluating the business concept from multiple angles. The validated production process, third-party assessments of the cells, and the development of a comprehensive business plan have facilitated productive discussions with investors about the next steps.
While these achievements are promising, it is important to note that the iMonoMac cell product is intended for a highly regulated market. This underscores the need for further assessment and comparison of the product against existing market offerings. Despite these challenges, iPYRO has made a significant step towards market entry, demonstrating the potential and opportunities for the iMonoMac product.
While these achievements are promising, it is important to note that the iMonoMac cell product is intended for a highly regulated market. This underscores the need for further assessment and comparison of the product against existing market offerings. Despite these challenges, iPYRO has made a significant step towards market entry, demonstrating the potential and opportunities for the iMonoMac product.