Periodic Reporting for period 2 - ACROBAT (TowArd demoCRatization Of ev-BAsed Therapies)
Okres sprawozdawczy: 2023-05-01 do 2024-04-30
Extracellular vesicles (EVs) or exosomes are subcellular entities released by cells. It is becoming widely known that EVs are as effective as cell therapies for tissue regeneration for diseases such as stroke, heart failure, arthritis while being safer and easier for supply chains. Therefore, they could be the key to the future health of an ageing population and are increasingly explored by many stakeholders.
However, the ability to manufacture quantities of EVs compatible with human use is a major challenge for the diffusion of this innovation. Indeed, the hindrances to overcome for rendering EV-based therapies clinically feasible are a cost-effective large-scale standardized EV production platform complying with regulatory issues and Good Manufacturing Practices (GMP). Existing production methods have low yields, are not all scalable and are very time consuming, rarely GMP compliant, making clinical translation of EV-based therapeutics difficult.
EVerZom addressed this challenge with the ambition of developing the first European innovative EV-platform covering the entire technological value chain from the cell source to the administration to patients. This platform is organized around four technological bricks: i. mother cell modification, ii. EV generation, iii. EV engineering and iv. EV formulation. The ACROBAT project is focused on EV generation brick with the objective to develop a GMP-compliant EV-bioproduction for further clinical development. This brick is on a patented technology and over 10 years of academic research in nano and biotechnologies, that relies on a unique bioinspired physically triggered production technology that enables to produce 10 times more EVs in 1/10th of the time compared to current production methods. It is an innovative, cost effective, scalable standardized EV production process.
However, the ability to manufacture quantities of EVs compatible with human use is a major challenge for the diffusion of this innovation. Indeed, the hindrances to overcome for rendering EV-based therapies clinically feasible are a cost-effective large-scale standardized EV production platform complying with regulatory issues and Good Manufacturing Practices (GMP). Existing production methods have low yields, are not all scalable and are very time consuming, rarely GMP compliant, making clinical translation of EV-based therapeutics difficult.
EVerZom addressed this challenge with the ambition of developing the first European innovative EV-platform covering the entire technological value chain from the cell source to the administration to patients. This platform is organized around four technological bricks: i. mother cell modification, ii. EV generation, iii. EV engineering and iv. EV formulation. The ACROBAT project is focused on EV generation brick with the objective to develop a GMP-compliant EV-bioproduction for further clinical development. This brick is on a patented technology and over 10 years of academic research in nano and biotechnologies, that relies on a unique bioinspired physically triggered production technology that enables to produce 10 times more EVs in 1/10th of the time compared to current production methods. It is an innovative, cost effective, scalable standardized EV production process.
Previous research has enabled us to identify the Kolmogorov length as a parameter governing the massive EV release in our technology. We have explored the mechanical stress range susceptible to induce EV production without affecting cell survival which enables us to select and patent the Kolmogorov length range with the optimal mechanical constraint with a good compromise between efficiency and cell survival. For adipose derived stem cells, we have selected the optimal Kolmogorov length. By keeping the optimal Kolmogorov length constant, a first scale-up from 0.1L to 1L was achieved. By keeping the optimal Kolmogorov length constant, we were able to achieve a scale-up for human MSCs from adipose tissue to 10L in a clinical compliant bioreactor with consistent yield, providing the needed batches for clinical phase I trials.
The ACROBAT project had two main objectives: (1) transfer the production of adipose derived stem cells to GMP environment and validate EV quality control, with the aim of producing a first GMP pilot batch; and (2) expand the platform by producing large-scale batches (10L) of various adherent and suspension cell types.
The 10L manufacturing scale is enough to provide EV developers with batches to support phases I/II clinical studies. Since there are currently very few EV GMP-compliant production capacities in Europe, the GMP certification was a key milestone for EVerZom, positioning it as a pioneer in this field. We performed a clinical grade EV production from human adipose stem cells successfully in April 2024
EVerZom planned to expand its technology to different cell lines/types to enlarge market opportunities and target all cell therapy and drug delivery players interested in EV approach. Expansion of EVerZom’s platform usefulness toward four different cell lines/types (three adherent cell lines and one suspension cell line/type) will strongly support the company to enlarge its know-how and expertise, increase its platform value and extend its market access by addressing all cell therapy biotech companies working on EV approaches, independently of their cell-based technology. Up to now, the production optimization and scaleup into 1L production system have been performed for two adherent cell lines and one suspension cell.
The ACROBAT project had two main objectives: (1) transfer the production of adipose derived stem cells to GMP environment and validate EV quality control, with the aim of producing a first GMP pilot batch; and (2) expand the platform by producing large-scale batches (10L) of various adherent and suspension cell types.
The 10L manufacturing scale is enough to provide EV developers with batches to support phases I/II clinical studies. Since there are currently very few EV GMP-compliant production capacities in Europe, the GMP certification was a key milestone for EVerZom, positioning it as a pioneer in this field. We performed a clinical grade EV production from human adipose stem cells successfully in April 2024
EVerZom planned to expand its technology to different cell lines/types to enlarge market opportunities and target all cell therapy and drug delivery players interested in EV approach. Expansion of EVerZom’s platform usefulness toward four different cell lines/types (three adherent cell lines and one suspension cell line/type) will strongly support the company to enlarge its know-how and expertise, increase its platform value and extend its market access by addressing all cell therapy biotech companies working on EV approaches, independently of their cell-based technology. Up to now, the production optimization and scaleup into 1L production system have been performed for two adherent cell lines and one suspension cell.
Thanks to the EIC Accelerator support and the ACROBAT project, we succeed to reach all of our milestones and expand our innovative EV platform.
We first were able to secure robust manufacturing with the first GMP pilot batch produced in 2024. Before the ACROBAT project, we already scaled our EV production into 10L cGMP bioreactor. Through the ACROBAT project, the process has been transferred into certified cleanroom, quality control has been defined, and characterization methods have been validated. This first reached milestone constitutes one of the cornerstones in the development of our therapeutic EV-based platform where the next key steps are the following ones:
- The production of supplementary clinical grade batches for the launch of our first in human and first clinical trial (expected in 2026).
- Further industrialization of our process: we will scale-up our process in 50L bioreactor and reproduce the identical transfer for GMP production. In addition, all the work performed in defining QC and validating of the characterization methods won't have to be repeated.
- Regulatory feedback with the submission of a Scientific Advice to the EMA.
The second reached milestone has enabled us to expand our EV bioproduction platform to different cell types, the first 10L bioreactors at high yield for HEK in adherence, endometrial MSC, THP1 and MSC umbilical cord were developed. A first long-term partnership was signed in 2023 for the production of EV from endometrial MSC. We plan to sign several other similar partnerships.
We first were able to secure robust manufacturing with the first GMP pilot batch produced in 2024. Before the ACROBAT project, we already scaled our EV production into 10L cGMP bioreactor. Through the ACROBAT project, the process has been transferred into certified cleanroom, quality control has been defined, and characterization methods have been validated. This first reached milestone constitutes one of the cornerstones in the development of our therapeutic EV-based platform where the next key steps are the following ones:
- The production of supplementary clinical grade batches for the launch of our first in human and first clinical trial (expected in 2026).
- Further industrialization of our process: we will scale-up our process in 50L bioreactor and reproduce the identical transfer for GMP production. In addition, all the work performed in defining QC and validating of the characterization methods won't have to be repeated.
- Regulatory feedback with the submission of a Scientific Advice to the EMA.
The second reached milestone has enabled us to expand our EV bioproduction platform to different cell types, the first 10L bioreactors at high yield for HEK in adherence, endometrial MSC, THP1 and MSC umbilical cord were developed. A first long-term partnership was signed in 2023 for the production of EV from endometrial MSC. We plan to sign several other similar partnerships.