Adrenomedullin assays and methods for determining mature andrendomedullin
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Publication Number
US-12228581-B2
Publication Date
2025-02-18
Expiration Date
Abstract
An in vitro method for therapy follow-up in septic patients wherein the concentration of mature ADM 1-52 and/or mature ADM 1-52-Gly in a sample of bodily fluid of said septic patient is determined using an assay containing two binders that bind to two different regions within the region of mature adrenomedullin and/or adrenomedullin-Gly that is amino acid 21-52-amid SEQ ID No. 1 or amino acid 21-52-Gly SEQ ID No. 2 wherein each of said regions contains at least 4 or 5 amino acids, and further assays and calibration methods.
Core Innovation
The described invention concerns an in vitro method for therapy in which a plasma or whole blood sample from a human patient suspected of having sepsis is used to form a complex. The complex comprises mature adrenomedullin (ADM) 1-52 and/or mature ADM 1-52-Gly in the patient sample and two antibodies that bind to two different regions within the region of mature adrenomedullin and/or adrenomedullin-Gly that is SEQ ID No. 1 or SEQ ID No. 2. Each of the regions comprises at least 4 or 5 amino acids, and the amount of complex formed is measured.
The method enables using the measured amount of complex for therapy-related decision-making. Patients are stratified according to the measurement, or in combination with at least one other clinical and/or laboratory parameter and/or clinical score, and treatment is provided for patients indicated to have sepsis. In a further aspect, treatment includes administering at least one treatment selected from steroids, vasopressors, antibiotics and fluid therapy after the amount of complex formed is measured.
The invention also addresses assay performance and sample handling for routine follow-up in sepsis therapy. It provides that the assay recognizes epitope regions (each comprising at least 4 or 5 amino acids) within ADM 21–352-amid (SEQ ID No. 1) or ADM 21–352-Gly (SEQ ID No. 2) using two binders recognizing two different epitope regions. The disclosed assay format supports sensitive measurement in plasma, whole blood, and bodily fluid samples, including sandwich immunoassay options.
A disclosed clinical basis is that the initial ADM measurement and the day-to-day kinetics/change of ADM during hospitalization show prognostic value for sepsis patients. The normal population median is described as about 24.7 pg/mL, and the analytical sensitivity is described as about 2 pg/mL with detection of 100% of healthy subjects. The document also discloses modeling using a cut-off threshold around about 70 pg/mL to indicate responders versus non-/responders, and it reports improved outcome prediction using ADM kinetics/change.
Claims Coverage
The independent claims are clm-00001, clm-00019, and clm-00020. Across these claims, the inventive core centers on forming and measuring an ADM complex in plasma or whole blood using two antibodies targeting two different epitope regions (SEQ ID No. 1 or SEQ ID No. 2), followed by stratified sepsis therapy, with treatment expressly not provided as a follow-up treatment. The independent claims collectively specify three main inventive feature sets.
Forming and measuring an ADM complex in plasma or whole blood for sepsis therapy
Forming a complex in a plasma or whole blood sample from a human patient suspected of having sepsis, wherein the complex comprises mature adrenomedullin (ADM) 1-52 and/or mature ADM 1-52-Gly in the sample and two antibodies that bind to two different regions within the region of mature adrenomedullin and/or adrenomedullin-Gly that is SEQ ID No. 1 or SEQ ID No. 2, wherein each of said regions comprises at least 4 or 5 amino acids; and measuring the amount of complex formed.
Stratifying patients based on the measured ADM complex amount and treating sepsis patients
Forming a complex in a plasma or whole blood sample from a human patient suspected of having sepsis, wherein the complex comprises mature adrenomedullin (ADM) 1-52 and/or mature ADM 1-52-Gly and two antibodies that bind to two different regions within the region of mature adrenomedullin and/or adrenomedullin-Gly that is SEQ ID No. 1 or SEQ ID No. 2, wherein each region comprises at least 4 or 5 amino acids; measuring the amount of complex formed; stratifying the human patients into groups according to the measurement or in combination with at least one other clinical and/or laboratory parameters and/or clinical score; and treating the human patient in a group indicated to have sepsis.
Administering sepsis therapies after measuring the ADM complex amount
Forming a complex in a plasma or whole blood sample from a human patient suspected of having sepsis, wherein the complex comprises mature adrenomedullin (ADM) 1-52 and/or mature ADM 1-52-Gly and two antibodies that bind to two different regions within the region of mature adrenomedullin and/or adrenomedullin-Gly that is SEQ ID No. 1 or SEQ ID No. 2, wherein said region comprises at least 4 or 5 amino acids; measuring the amount of complex formed; and administering at least one of the treatments from the group consisting of steroids, vasopressors, antibiotics and fluid therapy.
Across clm-00001, clm-00019, and clm-00020, claim coverage focuses on forming a mature ADM 1-52/mature ADM 1-52-Gly complex in plasma or whole blood using two antibodies that bind to two different epitope regions defined by SEQ ID No. 1 or SEQ ID No. 2 with regions comprising at least 4 or 5 amino acids, then measuring the amount of complex formed to guide sepsis therapy that is not provided as a follow-up treatment. clm-00019 further requires stratifying patients into groups before treating, while clm-00020 further requires administering specific therapy classes after measurement.
Stated Advantages
Provides prognostic value of initial ADM and improved outcome prediction using day-to-day ADM kinetics/change during hospitalization.
Allows sensitive measurement with an analytical sensitivity described as about 2 pg/mL detecting 100% of healthy subjects.
Supports routine sepsis therapy follow-up by measuring ADM from plasma or whole blood using two binders recognizing two different epitope regions.
Documented Applications
In vitro therapy follow-up in sepsis using measured mature ADM 1-52 and/or mature ADM 1-52-Gly complex amounts in patient plasma or whole blood.
Patient stratification into groups for sepsis therapy based on measured ADM complex amount and, optionally, other clinical or laboratory parameters or clinical score.
Prognostic assessment in ED sepsis patients using initial ADM measurement and ADM day-to-day kinetics/change during hospitalization.
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