Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Fusion protein or fusion polypeptide
Reexamination Certificate
1995-07-06
2003-11-25
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Fusion protein or fusion polypeptide
C424S133100, C424S134100, C424S185100, C530S387300
Reexamination Certificate
active
06652863
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to fusion compounds having reduced immunogenicity resulting from the addition to an immunogenic compound of an amino acid sequence that renders the compound less immunogenic. The amino acid sequence is found in human proteins. The present invention relates to a method of reducing the immunogenicity of compounds by the incorporation of an amino acid sequence, the presence of which results in a reduced immune response against the compound.
BACKGROUND OF THE INVENTION
The pharmaceutical use of immunogenic compounds, such as proteins and carbohydrates, for diagnosis or therapy in humans has enormous potential. A major concern, however, is that immunogenic compounds often elicit immune responses which could limit their effectiveness and, in some cases, cause dangerous allergic reactions. This is particularly true of non-human proteins. In addition, it is possible that even proteins with human amino acid sequences could be immunogenic, as in the cases where the protein is altered in structure or conformation as a consequence of manufacturing or where the protein is produced in foreign hosts due to inappropriate post-translational modification or improper folding. Moreover, many non-protein compounds elicit an immune response.
The immune system of the human to whom the immunogenic compound is administered recognizes the compound as “foreign” and mounts an immune response to remove it. The immune response includes the production of specific, high affinity antibodies which bind to and effect elimination of the immunogenic compound.
Monoclonal antibodies (Mabs) provide examples of the therapeutic uses of foreign proteins. Most Mabs are of murine origin, and have generally been found to be immunogenic when injected into humans. Attempts have been made to reduce the immunogenicity of murine Mabs by substituting human constant regions for the analogous murine regions to form chimeric antibodies or chimeric Mabs, or by going one step further and substituting human framework sequences for the murine counterparts in the variable regions of the antibodies (humanized antibodies or humanized Mabs). These approaches may reduce the immune response elicited by murine constant regions or frameworks, but may be ineffective in reducing immune responses directed against the variable regions or idiotypes of the Mabs. Indeed, there are several examples of chimeric Mabs eliciting immune responses directed against the variable regions (for example, B72.3 reported by Meredith, et al., (1992) J. Nucl. Medicine 33:23-29, and ch14.18 reported by Saleh, et al., (1992) Hum. Antibody Hybridoma 3:19-24). In fact, immune responses to the anti-variable region may be the rule rather than the exception. In these cases, another approach is required.
There is a need for therapeutic or diagnostic compounds which do not elicit either an immune response or which elicit a reduced immune response. There is a need for a method of reducing or eliminating the immunogenicity of therapeutic and diagnostic compounds.
The present invention provides reduced-immunogenic compounds which elicit either a reduced immune response or essentially no immune response in humans and a method of reducing the immunogenicity of compounds. Reduced-immunogenic compounds according to the present invention comprise an auto-antigenic amino acid sequence linked to an otherwise immunogenic protein. By associating an auto-antigenic amino acid sequence with an immunogenic protein, the human immune system mounts a reduced immune response against the compound or does not mount an immunogenic response against it all. Accordingly, these compounds can be administered as therapeutics or diagnostics with a reduction or elimination of the problems associated with the administration of immunogenic compounds.
SUMMARY OF THE INVENTION
The present invention relates to reduced-immunogenic fusion compounds which comprise immunogenic compounds linked to auto-antigenic sequences. The presence of the auto-antigenic sequence renders the compound less immunogenic. In addition, the present invention relates to a method of reducing the immunogenicity of an immunogenic compound by linking an auto-antigenic sequence to an otherwise immunogenic compound. The present invention also relates to recombinant nucleotide sequence that encoding auto-antigenic sequences and to essentially pure auto-antigenic peptides.
DETAILED DESCRIPTION OF THE INVENTION
The presence of antibodies in normal human sera which are specific for portions of degraded proteins, such as portions of endogenous proteins degraded by proteolytic enzymes, has been observed. There are many reports in the literature that refer to observed endogenous immunoreactivity to cleaved antibody fragments. This endogenous immunoreactivity to cleaved endogenous proteins is referred to herein as “preimmunity”. The antibodies involved in preimmunity immunoreactivity were initially described as “agglutinators” or “anti-Fab antibodies” (“&agr;FABA”). It is reported that preimmunity antibodies 1) are present in most individuals, 2) have varying titers across a population, 3) are not IgM or rheumatoid factors, 4) are fragment specific, and 5) are generally of low affinity. These antibodies can be generally described as a heterogenous group of antibodies that share the characteristic of recognizing endogenous protein fragments, usually the terminal portions of antibody fragments, which are exposed by protein degradation, usually proteolytic degradation.
Osterland, C. K. et al. (1963) Vos Sang 8:133, report a serum activity capable of “agglutinating” Fab- or F(ab′)
2
−
coated human erythrocytes. The reactivity is directed to epitopes that only become exposed after an immunoglobulin is cleaved by a proteolytic enzyme. That is, these antibodies recognize the degraded protein but not the intact protein.
Waller, M. et al., (1969) Immunochemistry 6:207-214, report that “natural antibodies” in human sera were able to differentiate Fab fragments produced by different enzymes. Different antibodies of this group were specific to different epitopes on Fab fragments which were generated i.e., exposed, by the specific cleavage that a specific Fab fragment underwent.
Ling, N. R. and P. Drysdale, (1981) Int. Archs. Allergy Appl. Immun. 66:459, report that F(ab′)
2
fragments of human, bovine, and rabbit polyclonal and of human IgG paraproteins of different subclass and light-chain type were coupled to human red cells and used to detect “agglutinator antibodies” in normal and pathological human sera. Such antibodies were reported to commonly occur and demonstrate specificity heterogeneity.
Persselin, J. E. and R. H. Stevens, (1985) J. Clin. Invest. 76:723, report that sera from rheumatoid arthritis patients contained two populations of antibodies directed against the Fab portion of pooled human IgG.
Heimer R., et al., (May 1985) Arthritis and Rheumatism 28(5):562, report an examination of the specificity of IgG anti-F(ab′)
2
antibodies in unfractionated sera of patients with rheumatoid arthritis and from affinity purified antibody preparations.
Persselin, J. E. and R. H. Stevens (1989) Mongr. Allergy 26:74, report a group of “autologous antibodies” that are directed against the Fab and F(ab′)
2
portions of human IgG. This group, which was reported to be prevalent in normal individuals and patients suffering a variety of disorders, was characterized to be a heterogenous group of antibodies with diverse biological properties and target specificities.
Although many of the reports of “natural antibodies” relate to the existence of such antibodies that specifically bind to IgG fragments, it is believed that groups these type of antibodies exist which bind to degraded portions of other endogenous proteins.
As used herein, the terms “agglutinators”, “agglutinating antibodies”, “natural antibodies”, “autologous antibodies”, “preimmunity antibodies” and “preimmune serum antibodies” are used interchangeably and are meant to refer to antibodies that are normally present in an i
Jordan Robert E.
Knight David M.
Wagner Carrie Lynne
Centocor, Inc.
Gambel Phillip
Hamilton Brook Smith & Reynolds P.C.
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