CN-122003493-A - Bioreactor for producing biomolecules

Abstract

The invention relates to a bioreactor (1) comprising a device (2) for producing biomolecules, wherein the device comprises at least one reaction tank (3) designed for synthesizing biomolecules. The reaction tank comprises a tube (4) describing a left-hand curve extending around at least one helical axis (Ah 1, ah 2) to form a series of loops, wherein the tube fluidly connects a feed inlet (5) of the at least one reaction tank with a discharge outlet (6) of the at least one reaction tank. The tube according to the invention is rotatable about an axis of rotation (Ar 1) such that when the tube is rotated about the axis of rotation liquid is allowed to flow from one loop to the other loop in a specific fluid flow direction (F1) from the feed inlet to the drain outlet.

Inventors

• Christopher Bonneville
• Flora Binder
• Nicholas Moniot
• Emmanuel dagger

Assignees

• 迪利科公司

Dates

Publication Date

20260508

Application Date

20241009

Priority Date

20231012

Claims (17)

1. 1. Bioreactor (1) comprising a biomolecule production device (2) comprising at least one reaction vessel (3) designed for synthesizing biomolecules, characterized in that the at least one reaction vessel comprises a conduit (4) defining a space curve extending around at least one helical axis (Ah 1, ah 2) to form a continuous loop, the conduit fluidly connecting a feed inlet (5) of the at least one reaction vessel with a discharge outlet (6) of the at least one reaction vessel, and in that the conduit is rotatable around a rotation axis (Ar 1) such that liquid can flow from one loop to the other loop in a certain fluid flow direction (F1) from the feed inlet to the discharge outlet when the conduit is rotated around the rotation axis, and in that the rotation axis is offset in parallel with respect to the at least one helical axis and/or at an angle with respect to the at least one helical axis.
2. 2. Bioreactor according to claim 1, characterized in that the conduit is designed to make a continuous 360 ° rotation in the same rotation direction in the manner of an archimedes spiral.
3. 3. Bioreactor according to claim 1, characterized in that the conduit is designed for continuous 180 ° rotation in opposite rotation directions.
4. 4. Bioreactor according to any one of the preceding claims, characterized in that the helical axis has an inclination angle (α) with respect to the horizontal plane, so that the liquid can be stored in the loop in which the liquid is located between two rotations of the catheter around the rotation axis.
5. 5. Bioreactor as in any claim hereinbefore, characterized in that the conduit is inclined such that the feed inlet is a high point of the at least one reaction vessel and the discharge outlet is a low point of the at least one reaction vessel.
6. 6. Bioreactor according to any one of the preceding claims, characterized in that the feed inlet comprises an upstream conduit section (9) and the discharge outlet comprises a downstream conduit section (10), the upstream and downstream conduit sections extending longitudinally along the axis of rotation of the conduit.
7. 7. Bioreactor as in any claim hereinbefore, characterized in that the production plant comprises a plurality of reaction vessels fluidically connected in series along the fluid flow direction.
8. 8. Bioreactor according to claim 7, characterized in that the production device comprises a double connector (12) designed for fluidly connecting two reaction vessels to each other, the double connector comprising two movable parts connected to the discharge outlet of one of the two reaction vessels and the feed inlet of the other reaction vessel, respectively, the double connector comprising two stationary parts arranged between the two movable parts to allow rotation of the two reaction vessels relative to the stationary parts, and comprising a central conduit section arranged between the two stationary parts, the production device comprising an injection device fluidly connected to the central conduit section and designed for injecting a fluid into the central section in the fluid flow direction.
9. 9. Bioreactor according to any one of the preceding claims, characterized in that the production plant comprises a storage tank (11) in fluid connection with the discharge outlet of the reaction vessel, the volume of which is equivalent to the volume of the plurality of loops of the vessel, the storage tank being designed for storing liquid from the reaction vessel.
10. 10. A method of producing a biomolecule in a bioreactor according to any one of the preceding claims, characterized in that the method comprises the steps of: a) Injecting (100) a volume of liquid reaction mixture corresponding to a sub-batch into the loop of the at least one reaction vessel of the production facility upstream in the direction of fluid flow through a feed inlet, B) Rotating (200) the conduit to move the liquid reaction mixture into the next annulus towards the discharge outlet, C) Repeating (400) steps a) and b) the same number of times as the number of sub-batches of biomolecules to be produced within a single batch of biomolecules, And characterized in that the method comprises a step (300) of stirring the conduit, performed after step a) and before step b), the stirring step comprising an incomplete rotation of the conduit about the rotation axis, to prevent the flow of liquid from one loop to the other.
11. 11. The method of producing biomolecules according to claim 10, wherein the volume of the liquid reaction mixture injected in step a) is smaller than the internal volume of the annular ring.
12. 12. A method of producing a biomolecule according to any one of claims 10 to 11, wherein the volume of liquid reaction mixture injected in step a) allows a gaseous fluid to pass from the feed inlet to the discharge outlet of the at least one reaction vessel.
13. 13. Method for producing a biomolecule according to any one of claims 10 to 12, wherein the rotation of an upstream reaction vessel in the fluid flow direction is faster than the rotation of another downstream reaction vessel in the fluid flow direction, such that a plurality of sub-batches distributed across a certain first number of consecutive loops (n 1) of the upstream reaction vessel are distributed across a certain second number of loops (n 2) of the downstream reaction vessel, the second number being smaller than the certain first number of loops, such that n1 is ≡2 and n2 < n1.
14. 14. A method of producing a biomolecule according to any one of claims 10 to 13, wherein each rotation of the conduit is 360 ° in the same direction of rotation.
15. 15. A method of producing a biomolecule according to any one of claims 10 to 14, wherein each rotation of the conduit is 180 ° and each rotation alternates the direction of rotation.
16. 16. A method of producing a biomolecule according to any one of claims 10 to 15, wherein the biomolecule produced is selected from RNA, DNA and proteins.
17. 17. A method of producing a biomolecule according to any one of claims 10 to 16, wherein the produced biomolecule is used as a therapeutic agent.

Description

Bioreactor for producing biomolecules Technical Field The present invention relates to the field of biomolecule production, and more particularly to a bioreactor comprising a biomolecule production device comprising at least one reaction vessel designed for synthesizing biomolecules. The invention also relates to a method for producing biomolecules in a bioreactor according to the invention. Prior Art Recent advances in science and technology have expanded the use of biological molecules to biological diagnostics and therapeutic treatments. The rise of new therapies for genetic mechanisms and protein expression opens up new opportunities for the use of biomolecules, especially in the development of innovative therapies (e.g. vaccines). In particular, despite numerous technical difficulties in production and storage, there is a great interest in mass production of messenger RNA (mRNA) vaccines. In this respect, document WO2022/261050 describes a novel bioreactor for continuous production of mRNA, in which the reaction vessel enables synthesis of large amounts of mRNA in vitro and affinity chromatography of the mRNA to purify it. Wherein continuous mRNA synthesis is achieved by using an injection device designed for continuous injection of reagents based on real-time measurement of reagent concentration in the container. However, this type of bioreactor cannot achieve an amplification of mRNA production because the reaction vessel is sized to synthesize some minimum amount of mRNA. In addition, mRNA recovered at the outlet of the reaction vessel is accompanied by a reagent residue that does not participate in mRNA production. Thus, while mRNA can be efficiently separated from these reagents using affinity chromatography, the bioreactor consumes very large amounts of expensive reagents, such as enzymes and dNTPs, relative to the amount of mRNA produced. Disclosure of Invention Accordingly, an object of the present invention is to solve the above-mentioned problems. To this end, the invention relates to a bioreactor comprising a biomolecule production device comprising at least one reaction vessel designed for synthesizing biomolecules, characterized in that the at least one reaction vessel comprises a conduit defining a space curve extending around at least one helical axis to form a continuous loop, the conduit fluidly connecting a feed inlet of the at least one reaction vessel with a discharge outlet of the at least one reaction vessel, and in that the conduit is rotatable around a rotation axis such that liquid can flow from one loop to another loop in a certain fluid flow direction from the feed inlet to the discharge outlet when the conduit is rotated around the rotation axis, and in that the rotation axis is offset in parallel with respect to the at least one helical axis and/or offset in angle with respect to the at least one helical axis. The basic idea of the present invention is to sequentially perform the synthesis of biomolecules in each loop of a reaction vessel, thereby enabling the production of one to more sub-batches of biomolecules. Thus, with the bioreactor according to the invention, it is possible to mix the multiple sub-batches produced to form a single batch of biomolecules of the desired size. The bioreactor according to the invention may also have the following features: -the catheter is designed to make a continuous 360 ° rotation in the same rotation direction in the manner of an archimedes spiral; -the conduit is designed to make successive 180 ° rotations in opposite directions; -the helical axis has an inclination with respect to the horizontal plane such that liquid can be stored in the loop in which it is located between two rotations of the catheter about the rotation axis; -the conduit is inclined such that the feed inlet is a high point of the at least one reaction vessel and the discharge outlet is a low point of the at least one reaction vessel; -the feed inlet comprises an upstream conduit section and the discharge outlet comprises a downstream conduit section, the upstream and downstream conduit sections extending longitudinally along the rotational axis of the conduit; -the production plant comprises a plurality of reaction vessels fluidly connected in series along the fluid flow direction; -the production device comprising a double connector designed for fluidly connecting two reaction vessels to each other, the double connector comprising two movable portions connected to a discharge outlet of one of the two reaction vessels and a feed inlet of the other reaction vessel, respectively, the double connector comprising two fixed portions arranged between the two movable portions to allow rotation of the two reaction vessels relative to the fixed portions, and comprising a central conduit section arranged between the two fixed portions, the production device comprising an injection device fluidly connected to the central conduit section and designed for injecting a fluid i