Clozapine immunoassay
Inventors
Salamone, Salvatore J. • Courtney, Jodi Blake • Sard, Howard • Spedaliere, Christopher
Assignees
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Publication Number
US-8771972-B2
Publication Date
2014-07-08
Expiration Date
Abstract
Novel conjugates and immunogens derived from clozapine and antibodies generated by these immunogens are useful in immunoassays for the quantification and monitoring of clozapine in biological fluids.
Core Innovation
Rapid, automated immunoassays are needed to quantify clozapine in human biological fluids for therapeutic drug management due to wide pharmacokinetic variability. Existing analytical methods such as LC/UV or LC/MS are described as labor-intensive, and the background states that no clozapine immunoassays exist. The described approach addresses the need for an immunoassay that determines clozapine in a sample while avoiding interference from clozapine metabolites.
The core of the invention is antibodies that are substantially selective for clozapine and do not substantially cross-react with or bind clozapine metabolites N-desmethylclozapine and clozapine-N-oxide, which are described as interfering species. The antibody is used in a competitive immunoassay format in which the presence of clozapine in the sample is determined by measuring the amount of a conjugate that is bound or unbound to the antibody.
Clozapine-selective antibodies are generated using immunogens and conjugate reagents built from clozapine derivatives having a defined compound formula with components B, Y, X, and p, where B is selected from —(C(O))—, —(C(O))—NH—, —(C(O))—O—, and —CH2—, Y is an organic spacing group, X is a terminal functional group capable of binding to a carrier, and p is an integer from 0 to 1. The defined clozapine derivative components are conjugated to immunogenic carriers including polyamine polymer and proteins such as KLH and BSA, and competitive binding is measured using the labeled or conjugate binding partner.
Claims Coverage
The partial content includes two independent claims: an immunoassay method and a kit. Each claim centers on two inventive elements: an antibody that is selectively reactive with clozapine and not substantially cross-reactive with N-desmethylclozapine and clozapine-N-oxide, and a defined carrier-conjugate reagent based on the specified compound formula (B, Y, X, p) with a carrier having a reactive thiol or amino group, followed by determining presence based on bound or unbound conjugate or providing the reagents in separate containers.
Selective clozapine immunoassay with non-cross-reactive antibody and defined carrier conjugate
Providing a mixture comprising a sample, an antibody selectively reactive with clozapine and not substantially cross-reactive with N-desmethylclozapine and clozapine-N-oxide, and a conjugate of a carrier having either a reactive thiol or amino group with a compound of the formula wherein B is —(C(O))—, —(C(O))—NH—, —(C(O))—O—, or —CH2—, Y is an organic spacing group, X is a terminal functional group capable of binding to the carrier, and p is an integer from 0 to 1 (or salts thereof), causing binding of clozapine in the sample and said conjugate in the mixture to the antibody, and measuring the amount of said conjugate bound or unbound to the antibody to determine the presence of clozapine.
Patient-sample clozapine detection kit with defined conjugate and non-cross-reactive antibody
Providing a kit for determining the presence of clozapine in a patient sample comprising reagents in separate containers, one reagent being a conjugate of a carrier having either a reactive thiol or amino group with a compound of the formula wherein B is —(C(O))—, —(C(O))—NH—, —(C(O))—O—, or —CH2—, Y is an organic spacing group, X is a terminal functional group capable of binding to the carrier, and p is an integer from 0 to 1 (or salts thereof), and the second container containing an antibody selectively reactive with clozapine and not substantially cross-reactive with N-desmethylclozapine and clozapine-N-oxide.
Across the independent claims, coverage is directed to competitive clozapine detection using a substantially selective anti-clozapine antibody that does not substantially cross-react with N-desmethylclozapine or clozapine-N-oxide, in combination with a conjugate reagent formed from a carrier with a reactive thiol or amino group and a clozapine-derivative compound defined by B, Y, X, and p, with determination based on bound versus unbound conjugate or via reagent kit presentation in separate containers.
Stated Advantages
Enables rapid, automated immunoassay detection of clozapine in human biological fluids for therapeutic drug management.
Avoids interference by using antibodies that are substantially selective for clozapine and not substantially cross-reactive with N-desmethylclozapine and clozapine-N-oxide.
Uses a competitive immunoassay format that determines the presence of clozapine by measuring the amount of conjugate bound or unbound to the antibody.
Documented Applications
Therapeutic drug management by quantifying or determining the presence of clozapine in human biological fluids or patient samples.
Interference control in clozapine immunoassay detection by addressing the metabolites N-desmethylclozapine and clozapine-N-oxide.
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