Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Free from infectious agents
Reexamination Certificate
2001-06-14
2004-02-24
Saunders, David (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Free from infectious agents
C422S021000, C422S022000, C422S023000, C436S548000, C530S390100
Reexamination Certificate
active
06696060
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for sterilizing preparations of monoclonal immunoglobulins to reduce the level of active biological contaminants therein, such as viruses, bacteria, yeasts, molds, mycoplasmas, prions and/or parasites.
BACKGROUND OF THE INVENTION
Antibodies are produced by organisms in response to exposure to foreign substances that the body perceives as a threat. Antibodies, or as they are collectively known, immunoglobulins (Ig), are proteins secreted by cells of the immune system known as B-cells or plasma cells. The structure of immunoglobulins is complex, but is well characterized. In brief, each immunoglobulin consists of a complex of protein chains known as the heavy and light chains. Each heavy chain is linked to a single light chain via disulfide bonds. The resulting complex is in turn linked by additional disulfide bonds to an identical heavy-light chain complex. This basic unit can be assembled by the cell into several specialized forms by varying the structure and number of heavy chains. Different heavy chain structures produce differing molecules, known as “classes” of immunoglobulins. These classes may also have different numbers of the basic units described above.
The production of these various physical forms of the immunoglobulin molecule occurs in a sequential manner. During this process, the specificity of the molecule for a single molecule or antigen remains unchanged. This is because the changes described above all occur to the portion of the immunoglobulin molecule that is not involved in determining the specificity of the particular immunoglobulin molecule. This “hypervariable region” is subject to an unusually high degree of recombination events during B-cell maturation. These recombination events cease prior to the production of the first immunoglobulin molecule by the cell. The result is that from a relatively small number of variable region genes, the body generates a large number of potential immunoglobulin molecules of differing specificities.
Once a B-cell encounters a molecule to which its own immunoglobulin molecule binds (an “antigen”), and upon receiving signals from other cells in the immune system, the B-cell first multiplies into a large number of identical cells, (collectively referred to as a clone) and then differentiates into an immunoglobulin-secreting plasma cell. In this way, the extremely large number of potential immunoglobulin molecules that might be manufactured is limited to only those molecules that recognize antigens to which the body must respond.
The vast array of immunoglobulin specificities that are produced results in an ongoing protection for the body against infection from those organisms that the body has made immunoglobulins against in the past. Taken in sum, the result is that the immunoglobulins contained in the plasma from a single donor may have millions of useful immunoglobulin specificities. A preparation of immunoglobulins from plasma is thus referred to as a polyclonal immunoglobulin preparation, since it contains the immunoglobulin molecules produced by all of the plasma cell clones in the body.
Polyclonal immunoglobulins are particularly useful for treating human disease in which the ability to produce Ig is absent or impaired. Since all plasma cell clones are affected, a mixture of all the immunoglobulin specificities found in the plasma is needed to correct the deficiency. In contrast, when an extreme degree of specificity is required, or when a single defined therapeutic goal is sought, polyclonal immunoglobulins are not the best solution. Instead, an immunoglobulin preparation consisting of the immunoglobulin molecules produced by a single clone with the desired specificity is the most precise and predictable solution. Such a preparation is known as a monoclonal immunoglobulin.
Monoclonal immunoglobulin have many differences as compared to polyclonal immunoglobulins. Their monospecificity makes them very precise when used as detection reagents. As therapeutics, they are free of confounding or dangerous side effects that arise from polyclonal immunoglobulin preparations, such as the introduction of immunoglobulins of unwanted specificities being introduced into the patient. Their physical characteristics may also be different. Since each monoclonal immunoglobulin has a unique and unvarying structure, its potential for stability, degradation, aggregation, temperature sensitivity and other characteristics are unique and unchanging. Once a suitable monoclonal immunoglobulin has been chosen for production, its characteristics will not change, and it thus can be manufactured with great consistency and assurance of its performance and storage characteristics. The ability to tailor production volumes to product requirements also makes monoclonal immunoglobulin a highly desirable alternative to polyclonal immunoglobulins.
Monoclonal immunoglobulin preparations are made in one of three general fashions. The first involves production in a cell culture system, the second uses an animal as a temporary bioreactor for monoclonal immunoglobulin production, and the third involves inserting the gene for a desired monoclonal immunoglobulin into an animal in such a manner as to induce continuous production of the monoclonal immunoglobulin into a fluid or tissue of the animal so that it can be continuously harvested (transgenic production).
Each of these methods may result in contamination of the product by pathogens. In the first method, the cells producing the monoclonal immunoglobulin may harbour undetected viruses that can be produced in the culture system. Contamination of the culture system by bacteria, yeast or mold may also occur.
Both of the remaining methods involve the use of an animal to either serve as a host for the monoclonal immunoglobulin-producing cells or as a bioreactor to manufacture the monoclonal immunoglobulin product itself. Obviously, these products face the risk of contamination by pathogens infecting or harboured by the host animal. Such pathogens include, viruses, bacteria, yeasts, molds, mycoplasmas, and parasites, among others.
Consequently, it is of utmost importance that any biologically active contaminant in the monoclonal immunoglobulin product be inactivated before the product is used. This is especially critical when the product is to be administered directly to a patient. This is also critical for various monoclonal immunoglobulin products which are prepared in media which contain various types of plasma and which may be subject to mycoplasma or other viral contaminants.
Previously, most procedures have involved methods that screen or test products for a particular contaminant rather than removal or inactivation of the contaminant from the product. Products that test positive for a contaminant are merely not used. Examples of screening procedures include the testing for a particular virus in human blood from blood donors. Such procedures, however, are not always reliable and are not able to detect the presence of viruses in very low numbers. This reduces the value or certainty of the test in view of the consequences associated with a false negative result. False negative results can be life threatening in certain cases, for example in the case of Acquired Immune Deficiency Syndrome (AIDS). Furthermore, in some instances it can take weeks, if not months, to determine whether or not the product is contaminated.
In conducting experiments to determine the ability of technologies to inactivate viruses, the actual viruses of concern are seldom utilized. This is a result of safety concerns for the workers conducting the tests, and the difficulty and expense associated with the containment facilities and waste disposal. In their place, model viruses of the same family and class are used.
In general, it is acknowledged that the most difficult viruses to inactivate are those with an outer shell made up of proteins, and that among these, the most difficult to inactivate are those of the smallest size. This has been shown to be true for gamma irradiati
Burgess Wilson H.
Drohan William N.
Forng Ren-Yo
Grieb Teri
MacPhee Martin J.
Clearant Inc.
Fleshner & Kim LLP
Saunders David
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