WO1993000807A1 - Procede de stabilisation de biomateriaux - Google Patents
Procede de stabilisation de biomateriaux Download PDFInfo
- Publication number
- WO1993000807A1 WO1993000807A1 PCT/US1992/005643 US9205643W WO9300807A1 WO 1993000807 A1 WO1993000807 A1 WO 1993000807A1 US 9205643 W US9205643 W US 9205643W WO 9300807 A1 WO9300807 A1 WO 9300807A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drying
- protein
- freezing
- group
- biomaterial
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
- A01N1/0221—Freeze-process protecting agents, i.e. substances protecting cells from effects of the physical process, e.g. cryoprotectants, osmolarity regulators like oncotic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
Definitions
- the invention described herein relates to a method of stabilizing biomaterials, especially labile proteins, during drying or freeze-drying using stabilizing components to achieve enhanced protection.
- Freeze-drying processes have been used with limited degrees of success in protein preservation due to protein denaturation and/or inactivation caused by the freezing or sublimation steps. Even under conditions where the freezing phase of the process is not damaging (i.e., the protein can withstand freezing stress or a cryoprotectant is used) , the subsequent removal of water from the sample by sublimation of the frozen sample (drying phase) can lead to irreversible damage.
- additives are also used to improve the stability of the protein during long- term storage of the dried product.
- proteins are inherently stable against acute freeze-drying stress, and only need to be protected during the subsequent storage of the dried product.
- Human growth hormone and ribonuclease A are examples of this type of protein.
- the current invention relates to a method of employing solutes which stabilize labile proteins and other biomaterials during the acute stresses encountered during freeze- drying. Additionally, the compositions of the present invention enhance overall protein recovery after freeze- drying and storage of the dried product. The solute mixture that confers stability against acute stresses during freeze-drying also aids in long-term storage of the protein or other biomaterial.
- Damage to freeze-dried proteins is manifested after rehydration, for example, as a loss of protein solubility, aggregation upon rehydration, loss of activity in appropriate bioassays (e.g., stimulated or depressed mitosis or activity of cells induced by growth factors, or antigen binding by an antibody) or in the case of enzymes, a loss of catalytic activity.
- bioassays e.g., stimulated or depressed mitosis or activity of cells induced by growth factors, or antigen binding by an antibody
- enzymes e.g., a loss of catalytic activity.
- the latter parameter is an extremely sensitive measure of protein damage.
- An enzyme that is fully soluble and has not aggregated may still display a loss of catalytic activity if it has undergone damaging conformational changes.
- assays for characterizing catalytic activity are straightforward and are not subjected to the variability and vagaries of bioassays, such as those employed for hormones and growth factors.
- enzymes are ideal model systems for studies on the stabilization of proteins during freeze drying.
- One object of the present invention is to provide a method of stabilizing proteins against both the freezing and drying stresses encountered during lyophilization, preferably by employing a two-component system. Whereas component one or two when used alone may not provide adequate protection of the protein both during freezing and drying, when these components are used in combination, protection during freezing and drying is obtained. Thus with embodiments of this method, synergistic protection of the protein can be realized during freeze-drying, with component one providing primary stabilization against freezing and component two primarily protecting during the drying phase.
- One advantage of the present invention is to obtain freeze- drying stabilization by employing solutes that would not normally be expected to protect labile proteins during freeze-drying.
- An object of the present invention is to speed and simplify development of freeze-drying protocols for the stabilization of labile proteins.
- An improved method for stabilizing biomaterials, especially labile proteins, during freeze- drying is disclosed, wherein stabilization is realized employing an additive system, preferably a two-component system.
- one component may serve as a cryoprotectant to protect the protein against damage due to freezing, while conferring minimal protection during the subsequent drying phase.
- Component two may be selected and employed to confer minimal protection during freezing, and when used alone affords no protection or is damaging to the protein during drying.
- DETAILED DESCRIPTION Freeze-drying involves lyophilization and refers to the process by which an aqueous solution of a protein and additives is frozen, after which the water is removed by sublimation at low pressure. Subsequent rehydration of the dried protein preparation is typically necessary to use the protein and to assay the effect of the processing steps on protein activity.
- the drying phase typically involves all stages of the sublimation process following freezing.
- Excipients and stabilizing solutes or additives are compounds that are added to the protein solution or suspension (broadly referred to herein as a "protein solution") prior to freeze-drying to improve the stability of the protein to the freeze-drying cycle, and to improve the storage stability of the dried product.
- the invention described herein relates to a method of employing preferably a two-component mixture of solutes to stabilize labile proteins against the stresses encountered by freeze-drying.
- the method also aids in overall protein recovery after freeze-drying and storage of the dried product. That is, the solutes that confer stability against acute stresses also aid in the long-term storage of the protein.
- Component one, used to stabilize the protein comprises a polymer which provides at least some cryoprotection for the protein.
- the cryoprotectant is preferably a compound that has the capacity to protect the protein during freezing and subsequent thawing or during the freezing phase of a freeze-drying process. Some cryoprotectants also protect during the subsequent drying step of freeze-drying.
- Preferred examples of polymers that can serve as cryoprotectants for proteins include: polyethylene glycol, polyvinyl pyrrolidone, hydroxyethyl starch, dextran and ficoll.
- the polymers used herein can include compounds having a molecular weight of greater than about 500 daltons.
- Polyethylene glycol is a preferred polymer useful as component one because it is commonly used during protein purification and thus it often present in solution with a protein to be freeze-dried. Polyethylene glycol is useful in that t prevents the protein from sticking to the surface of the container in which it is present. A preferred level of polyethylene glycol is from about 0.5 to about 20%(w/v) of the suspension.
- Component two is a compound that when used alone may provide minimal if any protection for the protein during either freezing or drying, and may actually potentiate the protein damage when used alone. Examples of compounds that can be used as component two include:
- sugars e.g., trehalose, lactose, sucrose, glucose, galactose, maltose, mannose and fructose
- polyhydroxy alcohols e.g., mannitol, sorbitol and inositol
- amino acids e.g., glycine, alanine, proline and lysine
- methylamines e.g., trimethylamine-N- oxide, betaine and sarcosine.
- Some compounds suitable for use as the second component protect freeze-dried proteins under certain conditions, such as at specific initial concentrations (e.g., the influence of trehalose on freeze-dried phosphofructokinase; Carpenter and Crowe, Biochemistry 28:3916-3922, 1989), whereas others appear to be virtually ineffective at protecting labile proteins during freeze-drying (e.g., the influence of glycine on freeze-dried phosphofructokinase; Carpenter et al., Biochem, Biophys. Acta, 923: 109-115, 1987) .
- component two protects the protein during the drying phase of the freeze-drying process.
- a preferred level is from about 1 to about 300 mM.
- freeze-drying stabilization is not limited to sugars.
- Compounds such as polyhydroxy alcohols, amino acids and methylamines are surprisingly effective at stabiLizing proteins during the drying phase.
- component one can be comprised of one or more of the cryoprotectant solutes defined above.
- component two can be comprised of one or mo:-e of the above defined solutes.
- the invention described herein can also be used to stabilize other biological materials such as viruses or human, animal, or bacterial cells during freeze drying.
- proteins such as a growth factors, hormones, antibodies, antigens, enzymes, clotting factors, structural proteins and complement factors can be combined with components one and two as described herein and subjected to freeze- drying. Specifically, such proteins would include:
- CAMPATH-1, anti-TAC, etc. Polyclonal antibodies; Human IgM; and Human IgG.
- a labile biomaterial such as a liposome, cell organelle, vaccine, virus, bacteria, eukaryotic cell, platelet, living-cell viral vaccine, other subcellular element, genetic material or other biomaterial can be freeze-dried according to the embodiments described herein.
- a further embodiment of the present invention involves the use of the two component system described herein to stabilize proteins and other biomaterials against the detrimental effects of alternative means of drying, including spray drying or vacuum centrifugation.
- EXAMPLE 1 Rabbit muscle lactate dehydrogenase (M isozyme, 99+% homogeneous) was purchased as a crystalline suspension in ammonium sulfate (Sigma; St. Louis, Mo) . Prior to each experiment the lactate dehydrogenase (“LDH”) was dialyzed (4°C) for several hours against 10 rriM potassium phosphate buffer (pH 7.5 at 23°C) . An aliquot of the stock enzyme was added to the appropriate preparation of polyethylene glycol (MW 8000) (prepared in the 10 mM potassium phosphate buffer) to a final LDH concentration of 25 g/ml and 10% (wt/vol) of polyethylene glycol (PEG) .
- LDH lactate dehydrogenase
- Samples of various concentrations of PEG were obtained by diluting the above mixture with a solution containing 25 ⁇ g/ml of LDH in the buffer alone.
- 25 / -g/ml of LDH was prepared in the buffer containing 1% (wt/vol) PEG and 100 mM trehalose.
- Various concentrations of trehalose were obtained by diluting this mixture with a buffer solution containing 25 /-g/ml LDH and 1% PEG without trehalose.
- FREEZE-THA EXPERIMENTS A 75 ⁇ l aliquot of a given mixture was transferred to a 1.5 ml polypropylene Eppendorf test tube. A 10 ⁇ l sample was removed and assayed for LDH catalytic activity. This served as the pre-treatment control value. LDH catalytic activity was measured at 25°C.
- the 2.0 ml reaction mixture contained 80 mM Tris/Hcl buffer (pH 7.5), 100 mM KC1, 2 mM pyruvate, and 0.15 mM NADH. The remaining 65 ⁇ l aliquot in the test tube was frozen by immersion into liquid nitrogen for 30 seconds. Samples were then thawed at room temperature, immediately mixed and assayed for residual activity. The results are expressed as the percentage of the pre- treatment activity recovered after thawing.
- Fig. 1A demonstrate that PEG completely protects LDH from inactivation during freeze- thawing. Essentially full activity is recovered at all PEG concentrations tested. By contrast, PEG provides essentially no stabilization to the enzyme during freeze- drying. These results indicate that PEG is an ideal cryoprotectant for proteins, but that when used alone it does not have the capacity to stabilize freeze-dried proteins.
- trehalose either alone or in combination with 1% PEG
- Fig. IB The influence of trehalose (either alone or in combination with 1% PEG) on LDH stability during freeze- thawing is shown in Fig. IB.
- the combination of trehalose and 1% PEG provides almost full protection for the enzyme during freeze-thawing.
- trehalose alone provides almost no protection during freeze-thawing.
- Fig. 1C shows the effect of trehalose alone and trehalose in combination with 1% PEG on the stability of LDH during freeze-drying.
- Trehalose alone provides no stabilization and actually appears to cause additional damage to the enzyme during freeze-drying.
- trehalose is used in combination with 1% PEG (which alone provides only minimal protection) almost 100% of the LDH activity is retained after freeze-drying.
- PEG is the solute comprising component one, which fully protects against damage induced by freezing, while conferring minimal if any protection during the subsequent drying phase.
- Trehalose is the solute comprising component two, which confers minimal protection during freezing, and when used alone affords no protection and/or is damaging during drying.
- trehalose provides almost complete protection during the drying phase.
- Fig. 2A The influence of lactose (either alone or in combination with 1% PEG) on LDH stability during freeze-thawing is shown in Fig. 2A.
- the combination of lactose and 1% PEG provides protection for the enzyme during freeze-thawing.
- lactose alone provides almost no protection during freeze-thawing.
- Fig. 2B shows the effect of lactose alone and lactose in combination with 1% PEG on the stability of LDH during freeze-drying. Lactose alone provides no stabilization and appears to cause additional damage to the enzyme during freeze-drying.
- lactose is used in combination with 1% PEG (which alone provides only minimal protection) the LDH is stabilized during freeze-drying.
- Synergistic protection by the two components is realized during freeze-drying, with PEG providing stabilization against damage during freezing and lactose protecting during the drying phase.
- EXAMPLE 3 Samples were prepared and treated as described in Example 1, except that glucose was substituted for trehalose and served as component two.
- the influence of glucose (either alone or in combination with 1% PEG) on LDH stability during freeze-thawing is documented in Fig. 3A.
- the combination of glucose and 1% PEG provides protection for the enzyme during freeze-thawing.
- Fig. 3B shows the effects of glucose alone and glucose in combination with 1% PEG on the stability of LDH during freeze-drying.
- Glucose alone provides no stabilization and actually appears to cause additional damage to the enzyme during freeze-drying.
- glucose is used in combination with 1% PEG (which alone provide only minimal protection) the LDH is stabilized during freeze-drying.
- Fig. 4A The influence of glycine (either alone or in combination with 1% PEG) on LDH stability during freeze-thawing is shown in Fig. 4A.
- the combination of glycine and 1% PEG provides protection for the enzyme during freeze-thawing.
- Fig. 4B shows the effects of glycine alone and in combination with 1% PEG on the stability of LDH during freeze-drying.
- Glycine alone provides no stabilization and actually fosters additional damage to the enzyme during freeze-drying.
- glycine is used in combination with 1% PEG (which alone provide only minimal protection) the LDH is greatly stabilized during freeze-drying.
- Synergistic protection is realized during freeze-drying, with PEG providing stabilization against damage during freezing and glycine protection during the drying phase.
- EXAMPLE 5 Samples were prepared and treated as described in Example 1. Mannitol was substituted for trehalose and served as component two. The influence of mannitol (either alone or in combination with 1% PEG) on LDH stability during freeze-thawing is shown in Fig. 5A. The combination of mannitol and 1% PEG provides protection for the enzyme during freeze-thawing. By contrast, mannitol alone provides almost no protection during freeze-thawing. Fig. 5B shows the effects of mannitol alone and in combination with 1% PEG on stability of LDH during freeze-drying. Mannitol alone provides no stabilization and actually fosters additional damage to the enzyme during freeze-drying. By contrast, when mannitol is used in combination with 1% PEG (which alone provide only minimal protection) the LDH is greatly stabilized during freeze-drying.
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Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US72559391A | 1991-07-03 | 1991-07-03 | |
US725,593 | 1991-07-03 |
Publications (1)
Publication Number | Publication Date |
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WO1993000807A1 true WO1993000807A1 (fr) | 1993-01-21 |
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PCT/US1992/005643 WO1993000807A1 (fr) | 1991-07-03 | 1992-07-02 | Procede de stabilisation de biomateriaux |
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WO (1) | WO1993000807A1 (fr) |
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