Stabilized antibody-containing preparations

#The present invention relates to antibody-containing preparations, particularly stabilized antibody-containing preparations with low loss of active ingredients even after long-term storage. The present invention also relates to processes for preparing protein-containing stabilized preparations, comprising adjusting the pH with a basic amino acid or a basic amino acid derivative or a salt thereof.

#A number of injectable protein-containing preparations are supplied to the market, in which various measures are taken to provide stabilized protein-containing preparations with low loss of active ingredients even after long-term storage. Protein-containing preparations are prepared by dissolving active ingredients and various additives such as diluents, solubilizers, excipients, soothing agents, buffering agents, sulfur-containing reducing agents, antioxidants, stabilizers, surfactants, etc. in a buffer.

#A problem generally associated with the storage of proteins stored as concentrated solutions is their deterioration as exemplified by the formation of insoluble aggregates and that must be prevented.

#FIG. 1 shows the results of native gel electrophoresis showing aggregation when antibody hPM-1 dissolved in 19 mM sodium phosphate, 0.2 M NaCl, pH 6.5 was heat-treated at 75° C. (electrophoretogram).

#FIG. 2 shows the results of native gel electrophoresis showing the effect of the type of buffer on aggregation (electrophoretogram).

#FIG. 3 shows the results of native gel electrophoresis showing the effect of adding 50 mM NaCl into buffers and heating on aggregation (electrophoretogram).

#Antibodies used in stabilized preparations of the present invention are preferably monoclonal antibodies, which may be prepared by any process. Monoclonal antibodies can be basically constructed by known techniques as follows. A suitable host is immunized with an immunizing antigen according to a standard immunization technique, and the resulting immunized cells are fused to known parent cells by a standard cell fusion technique, and then the fused cells are screened for monoclonal antibody-producing cells by a standard screening method.

#Antibodies contained in stabilized preparations of the present invention include, but not limited to, anti-IL-6 receptor antibodies, anti-HM1.24 antigen monoclonal antibodies, anti-parathyroid hormone related peptide antibodies (anti-PTHrP antibodies), anti-tissue factor antibodies, etc. For example, anti-IL-6 receptor antibodies include PM-1 (Hirata et al., J. Immunol. 143:2900-2906, 1989), AUK12-20, AUK64-7 or AUK146-15 (International Publication No. WO92/19759).

#Monoclonal antibodies are not limited to those produced by hybridomas, but also include chimeric antibodies obtained by artificial modifications to lower heteroantigenicity to human or for other purposes. Reshaped humanized antibodies can also be used in the present invention, which are obtained by replacing the complementarity-determining regions of a human antibody by the complementarity-determining regions of a non-human mammalian antibody such as a mouse antibody by standard gene recombination techniques also known. These known techniques can be used to obtain reshaped humanized antibodies.