Chemistry: molecular biology and microbiology – Maintaining blood or sperm in a physiologically active state...
Reexamination Certificate
2001-01-10
2003-04-15
Weber, Jon P. (Department: 1651)
Chemistry: molecular biology and microbiology
Maintaining blood or sperm in a physiologically active state...
C435S173300
Reexamination Certificate
active
06548242
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns a process for rendering a biological composition substantially free of enveloped and non-enveloped viruses contained therein without substantial disruption or inactivation of cells contained therein and without significant loss of labile proteins or other valuable biological components also contained therein.
2. Description of Related Art
The problems associated with the application of virucidal procedures to biological compositions and the efforts to date to overcome these problems, including the application of light and chemical agents is reviewed briefly in U.S. Pat. No. 5,120,649, the disclosure of which is incorporated herein by reference. See column 1, line 27, through column 4, line 41, therein.
Various photodynamic sterilization techniques have been evaluated for inactivating viruses in cellular components of blood. Although many of these appear promising for the treatment of red cell concentrates (Matthews et al., “Photodynamic therapy of viral contaminants with potential for blood banking applications”, in
Transfusion
, 28:81-83 (1988); O'Brien et al., “Evaluation of merocyanine 540-sensitized photoirradiation as a means to inactivate enveloped viruses in blood products”, in
J. Lab. Clin. Med
., 116:439-47 (1990); and Horowitz et al., “Inactivation of viruses in blood with aluminum phthalocyanine derivatives”, in
Transfusion
, 31:102-8 (1991)), photodynamic viral inactivation methods involving solely oxygen dependent reactions have so far proved inappropriate for the treatment of platelet concentrates (Proudouz et al., “Inhibition by albumin of merocyanine 540-mediated photosensitization of platelets and viruses”, in
Transfusion
, 31:415-22 (1991), Dodd et al., “Inactivation of viruses in platelet suspensions that retain their in vitro characteristics: comparison of psoralen-ultraviolet A and merocyanine 540-visible light methods”, in
Transfusion
, 31:483-90 (1991); and Horowitz et al., “Inactivation of viruses in red cell and platelet concentrates with aluminum phthalocyanine (AIPc) sulfonates”,
in Blood Cells
, 18:141-50 (1992)).
One of the latest developments is the use of photoactive compounds. See, e.g., U.S. Pat. No. 5,120,649 and U.S. Ser. No. 07/706,919, filed May 29, 1991. Psoralen, together with UVA, has been shown to kill viruses in both cell-containing and cell-free solutions without undue damage to the valuable components needed for transfusion. Methylene blue, together with visible light, is being used to treat whole plasma. Phthalocyanines and other heme analogs, together with visible light, are being explored for treatment of red blood cell concentrates and other blood components.
Treatment with psoralens and long wavelength ultraviolet light (UVA) is known to produce various biochemical effects including oxygen independent interactions with nucleic acids (e.g., psoralen-DNA monoadduct formation and DNA crosslinking) and oxygen dependent reactions of a photodynamic nature (for review, see Gasparro, F. P. (Ed.) (1988)
Psoralen DNA Photobiology
, Vol I, Vol II, CRC Press, Boca Roton, Fla.). In contrast to the purely photodynamic procedures appropriate for red cells (above), the use of psoralens and UVA has demonstrated promise as a means of photoinactivating viral contaminants in platelet concentrates, although in most studies (Lin et al., “Use of 8-methoxypsoralen and long-wavelength ultraviolet radiation for decontamination of platelet concentrates”, in
Blood
, 74:517-525 (1989); and Dodd et al., supra, aminomethyl-trimethylpsoralen (AMT)), the combination of high levels of virus inactivation and the maintenance of platelet function were possible only when air was exchanged with nitrogen prior to UVA irradiation, a cumbersome procedure with inherent variability. However, it was recently demonstrated (Margolis-Nunno et al., “Virus Sterilization in Platelet Concentrates with Psoralen and UVA in the Presence of Quenchers”
Transfusion
, 22:541-547 (1992)), that for the inactivation of ≧6.0 log
10
cell-free vesicular stomatitis virus (VSV) by AMT and UVA, the need for oxygen depletion as a means of protecting platelets could be obviated by inclusion of mannitol, a scavenger (quencher) of free radicals. (The addition of quenchers of type I (free radical mediated) or of type II (singlet oxygen mediated) photodynamic reactions is frequently used in other contexts to distinguish which active oxygen species produces a particular photodynamic effect.) Under the conditions used in that study, i.e., 25 &mgr;g/ml AMT and 30 minutes of UVA with 2 mM mannitol, the inactivation of cell-free VSV in air was in part oxygen dependent since equivalent virus kill (≧6.0 log
10
) with oxygen depleted required 3 to 4 times more UVA irradiation time (90 minutes to 2 hours).
However, while these methods achieved a high level of kill of cell-free lipid enveloped viruses and of actively replicating, cell-associated virus, non-enveloped viruses and latent cell-associated viruses were not killed to a high extent under the conditions reported therein. Therefore, there was the need to effect the kill of these latter virus forms without causing significant damage to the desired, valuable components in the biological mixture. Conditions which result in the kill of ≧10
6
infectious doses of latent or non-enveloped virus have been shown to modify red blood cells and platelets and result in compromised recovery of labile proteins such as factor VIII.
One of the most successful of the numerous methods developed to inactivate viruses in biological fluids is treatment with organic solvents and detergents; especially treatment with tri(n-butyl)phosphate (TNBP) and non-ionic detergents such as Tween 80 or Triton X-100. See, e.g., U.S. Pat. No. 4,540,573. This method results in excellent recovery of labile proteins, e.g., coagulation factor VIII and IX, while achieving a high level of virus kill, e.g., the killing of ≧10
6
to ≧10
8
ID, of enveloped viruses; however, little inactivation of non-enveloped viruses. See also, U.S. Pat. No. 4,481,189, wherein viral inactivation is by treatment with nonanionic detergent, alcohols, ethers, or mixtures thereof.
Other methods of virus inactivation commonly applied to biological fluids usable in a transfusion setting include treatment with heat at temperatures ≧60° C. or treatment with UVC together with B-propiolactone (B-PL). Each of these methods results either in a significant loss of labile proteins and/or incomplete virus killing. See, e.g., Horowitz, B.,
Biotechnology of Blood
, “Inactivation of viruses found with plasma proteins”, Goldstein, J., ed., Butterworth-Heinemann, Stoneham, 417-432, (1991). Additionally, adoption of B-PL has been slow because of its carcinogenicity. Newer methods intended to enhance virus safety are under development. The use of gamma irradiation has been explored in the laboratory, but, thus far, has not been used in the treatment of a commercially available product. See, Horowitz, B., et al., “Inactivation of viruses in labile blood derivatives 1. Disruption of lipid-enveloped viruses by tri(n-butyl)phosphate/detergent combinations”, in
Transfusion
, 25:516-521 (1985); and Singer et al., “Preliminary Evaluation of Phthalocyanine Photosensitization For Inactivation Of Viral Pathogens in Blood Products”, [abstract]
British J. Hematology
, March 23-25 (1988:Abs. 31). Filters are being developed which appear to remove ≧10
6
ID
50
of each of several viruses; however, small viruses, e.g., parvovirus or Hepatitis A virus, would not be expected to be removed completely. Moreover, it is not known whether these filters can be commercially produced with the consistency needed for virus safety.
In spite of these advances, there continues to be a need for novel methods that achieve a high level of kill of both enveloped and non-enveloped viruses without significant loss of labile proteins or other valuable biological components.
SUMMARY OF THE INVENTION
The overall objective of the present inventi
Chin Sing N.
Horowitz Bernard
Margolis-Nunno Henrietta
Williams Bolanle
Amster Rothstein & Ebenstein
New York Blood Center
Weber Jon P.
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