Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
1999-12-06
2004-01-20
Saunders, David (Department: 1644)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C435S007940, C435S962000, C530S388150
Reexamination Certificate
active
06680209
ABSTRACT:
BACKGROUND
Although it has long been recognized that human antibodies are superior to mouse antibodies for therapeutic use, the reverse has been thought to be the case for in vitro diagnostics. The different perceived roles of human and mouse antibodies reflect differences in their properties and methods of preparation. The principal hitherto recognized advantages of human antibodies relative to mouse antibodies are lack of human anti-mouse (HAMA) response on administration to a patient, longer in vivo half-life, and better interaction with human complement. All of these advantages account for the superiority of human antibodies to mouse antibodies for therapeutic use, but none is relevant to use of antibodies as reagents for in vitro diagnostics.
One of the principal advantages of mouse antibodies relative to human antibodies is ease of isolation. Despite improvements in methods for producing human antibodies in recent years, it has still generally been considered to have been a simpler matter to produce a mouse antibody than a human antibody, particularly when the desired antibody is sparsely represented in the total repertoire of antibodies that must be screened. Another advantage of mouse antibodies is that the mouse antibody constant region can be detected using a labelled anti-mouse antibody, typically prepared from another species, such as a goat, as a detection moiety. Such an antibody binds specifically to a mouse antibodies without binding to human antibodies present in the sample. Use of a secondary labelling moiety provides a useful format for detecting analytes in a human tissue sample. A comparable format cannot be used for human antibodies because an antibody against a human constant region would generate false positives by reacting with human antibodies in the sample. Because of their simplicity of isolation and compatibility with detection using a secondary labelling moiety, and because properties such as generation of a HAMA response, in vivo half life and complement activation are irrelevant for in vitro diagnostic purposes, mouse antibodies have been used for in vitro diagnostics to the virtual or total exclusion of human antibodies.
Although mouse antibodies are now in widespread use as diagnostic reagents, some problems have arisen when such antibodies are used to detect an analyte in a human sample. In some human samples, false positive or negative results are obtained due to the presence of HAMA or heterophilic antibodies in the sample. HAMA antibodies may be present in a human sample due to prior treatment of the patient from whom the sample was obtained with a mouse antibody (unrelated to the mouse antibody being used in diagnosis) or by environmental exposure to mouse antigens. Heterophilic antibodies are present in some patients as a response to certain pathogenic infections, such as Epstein Barr virus. Either HAMA or heterophilic antibodies in a sample can bind to a mouse antibody being used as a diagnostic reagent thereby generating a false positive signal. In sandwich assay formats, HAMA or heterophilic antibodies can form a bridge between immoblized and solution antibodies to generate a false positive, as in other formats. Alternatively, in a sandwich assay format, some HAMA or heterophilic antibodies may bind to the immobilized antibody without binding to the solution antibody (or vice versa) thereby preventing immobilized antibody and solution antibody from bridging to each other through an analyte and thus generating a false negative. In consequence, a significant number of assays performed on human clinical samples using mouse antibodies as the diagnostic reagent generate inaccurate results.
U.S. patent application Ser. No. 09/453,234, filed Dec. 1, 1999, U.S. Ser. No. 60/157,415, filed Oct. 2, 1999, PCT 98/06704, filed, Apr. 3, 1998, U.S. Ser. No. 08/835,159, filed Apr. 4, 1997 (now abandoned) and U.S. Ser. No. 08/832,985, filed Apr. 4, 1997 (now U.S. Pat. No. 6,057,098) are directed to related subject matter, and each is incorporated by reference in its entirety for all purposes.
SUMMARY OF THE INVENTION
The invention provides methods of detecting an analyte in a human sample containing human antibodies that specifically bind to antibodies from a nonhuman species. Such methods entail contacting the sample with a human antibody. The human antibody specifically binds to the analyte without specifically binding to the human antibodies that specifically bind to antibodies from a nonhuman species (e.g., HAMA or heterophilic antibodies present in the sample). Binding between the human antibody and the analyte is then detected. In some methods, the sample is contacted with a first human antibody that is immobilized on a support and a second human antibody in solution wherein the first and second human antibodies bind to different epitopes on the analyte; and the detecting step detects binding between the first and/or second human antibody to the analyte. In such methods, the second antibody is typically labelled. In some methods, the sample is contacted with a first population of human antibodies immobilized to a support and a second population of human antibodies in solution, wherein members from the first and second populations bind to different epitopes on the analyte.
Human antibodies used in such methods typically have affinities of at least 10
8
M
−1
, 10
9
M
−1
, 10
10
M
−1
, 10
11
M
−1
, 10
12
M
−1
for the analyte. Some human antibodies used in the methods are produced by expression of a recombinant construct in
E. coli
. Some such antibodies have immunoreactivities of at least 90%.
The invention further provides methods of detecting an analyte in a sample Such methods entail contacting the sample with a first human antibody immobilized to a solid phase, and a second human antibody in solution, wherein the first and second antibodies bind to different epitopes of the analyte if present in the sample. Binding of the analyte to the first and/or second antibodies is then detected. Binding indicates presence of the analyte in the sample. In such methods, the second antibody is typically labelled and the detecting detects binding of second antibody to the analyte. In some methods, the sample is contacted with a first population of human antibodies immobilized to a support and a second population of human antibodies in solution, wherein members from the first and second populations bind to different epitopes on the analyte in some methods, the binding of the first and/or second human antibodies to the analyte reaches equilibrium within an hour.
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Buechler Joe
Gray Jeff
Lonberg Nils
Valkirs Gunars
Biosite Incorporated
Saunders David
Townsend and Townsend / and Crew LLP
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