Autoantibodies to Septin-7 and diagnosis of neurological disease
Inventors
MISKE, Ramona • SCHARF, Madeleine • Komorowski, Lars • DENNO, Yvonne • Hahn, Stefanie • Radzimski, Christiane • Unger, Mandy • McKeon, Andrew • Pittock, Sean • Kryzer, Thomas • Lennon, Vanda • Honorat, Josephe
Assignees
Euroimmun Medizinische Labordiagnostika AG • Mayo Clinic in Florida
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Publication Number
US-11835519-B2
Publication Date
2023-12-05
Expiration Date
Abstract
A method for diagnosing a disease can include detecting, in a sample from a patient, an autoantibody binding to Septin-7. A polypeptide comprising Septin-7 or a variant thereof can be used for the diagnosis of a disease. Preferably, the polypeptide is used to detect an autoantibody binding to Septin-7 in a sample. A kit is useful for the diagnosis of a disease. The kit may include a polypeptide that includes Septin-7 or a variant thereof or a medical device that includes a polypeptide that includes Septin-7 or a variant thereof and an autoantibody to Septin-7.
Core Innovation
The disclosure relates to detecting an autoantibody binding to Septin-7 in a sample from a patient, while establishing an absence of autoantibody binding to one or more of Septin-3, Septin-5, Septin-6, or Septin-11. The patient has or is suspected of having a disease selected from paraneoplastic neurological syndrome (PNS), neuropathy, encephalopathy, encephalitis, encephalomyelopathy, myelopathy, episodic ataxia, bilateral carpal tunnel syndrome, and lumbosacral polyradiculopathy, or a tumor selected from ovarian cancer, breast adenocarcinoma, Non-Hodgkin lymphoma, carcinoid, myelodysplastic syndrome, and carcinoid of the lung.
The disclosure further provides Septin-7 polypeptides and variants as diagnostic reagents for autoantibody detection, including immobilized Septin-7 polypeptide on a carrier and configurations in which Septin-7 is included in a Septin complex. Septin complexes contain Septin-7 and at least one of Septin-3, Septin-5, Septin-6, or Septin-11, and the document also describes immunoassay and detection options and device and kit concepts for performing detection using the disclosed Septin-7 based reagents.
Experimental support indicates that patient sera show IgG binding to Septin-7 and to a Septin-3/5/6/7/11 complex, while showing no reactivity to complexes lacking Septin-7 and no anti-Septin-7 signal in healthy controls. Epitope mapping indicates recognition of N-terminal and C-terminal Septin-7 fragments, and a second cohort is described as differentiating from Septin-5 autoantibodies by tissue staining patterns and neuron staining behavior, including cerebrospinal fluid reactivity with live hippocampal neurons.
Claims Coverage
The partial content includes three independent claims. Across these independent claims, the inventive features center on Septin-7 autoantibody detection and discrimination from other Septin autoantibody binding, including configurations using Septin-7 polypeptides/variants and Septin complexes.
Detecting Septin-7 autoantibody with absence to other Septins for neurologic disease or specified tumors
Detecting, in a patient sample, an autoantibody binding to Septin-7 and an absence of the autoantibody binding to one or more of Septin-3, Septin-5, Septin-6, or Septin-11, where the patient has or is suspected of having a disease selected from paraneoplastic neurological syndrome (PNS), neuropathy, encephalopathy, encephalitis, encephalomyelopathy, myelopathy, episodic ataxia, bilateral carpal tunnel syndrome, and lumbosacral polyradiculopathy, or where the disease is a tumor selected from ovarian cancer, breast adenocarcinoma, Non-Hodgkin lymphoma, carcinoid, myelodysplastic syndrome, and carcinoid of the lung.
Contacting Septin-7 polypeptide with additional Septin(s) or a Septin-7 complex
Contacting a patient sample comprising an autoantibody to Septin-7 with a polypeptide comprising Septin-7 and one or more of Septin-3, Septin-5, Septin-6, Septin-11, or a complex containing the Septin-7 and one or more of Septin-3, Septin-5, Septin-6, Septin-11, where the patient has or is suspected of having a disease selected from paraneoplastic neurological syndrome (PNS), neuropathy, encephalopathy, encephalitis, encephalomyelopathy, myelopathy, episodic ataxia, bilateral carpal tunnel syndrome, and lumbosacral polyradiculopathy, or wherein the disease is a tumor selected from ovarian cancer, breast adenocarcinoma, Non-Hodgkin lymphoma, carcinoid, myelodysplastic syndrome, and carcinoid of the lung.
Isolating an autoantibody binding to Septin-7 via complex formation, isolation, detection, dissociation, and separation
Isolating an autoantibody binding to Septin-7 by contacting a sample comprising the autoantibody with a polypeptide comprising Septin-7 under conditions compatible with formation of a complex, isolating the complex, detecting the complex, dissociating the complex, and separating the autoantibody from the polypeptide.
Across the independent claims, the coverage centers on methods that detect or isolate autoantibodies that bind Septin-7, using discrimination from binding to other specified Septins and using formats involving Septin-7 polypeptides and Septin complexes containing Septin-7 with at least one additional Septin. The methods are tied to patient contexts for specified neurologic diseases and specified tumors, and include subsequent complex handling and detection for the isolation-focused claim.
Stated Advantages
Provides detection of autoantibody binding to Septin-7 with absence of binding to one or more of Septin-3, Septin-5, Septin-6, or Septin-11 for diagnostic purposes.
Differentiates from Septin-5 autoantibodies by tissue staining patterns and neuron staining behavior, including cerebrospinal fluid reactivity with live hippocampal neurons.
Experimental support indicates specificity for Septin-7 by observing IgG binding to Septin-7 and a Septin-3/5/6/7/11 complex while lacking reactivity to complexes lacking Septin-7 and showing no anti-Septin-7 signal in healthy controls.
Documented Applications
Diagnosing or detecting diseases in patients suspected of having paraneoplastic neurological syndrome (PNS), neuropathy, encephalopathy, encephalitis, encephalomyelopathy, myelopathy, episodic ataxia, bilateral carpal tunnel syndrome, and lumbosacral polyradiculopathy by detecting autoantibodies that bind Septin-7 with absence of binding to other specified Septins.
Diagnosing or detecting tumors in patients by detecting autoantibodies that bind Septin-7 while lacking binding to one or more of Septin-3, Septin-5, Septin-6, or Septin-11, where the tumor is selected from ovarian cancer, breast adenocarcinoma, Non-Hodgkin lymphoma, carcinoid, myelodysplastic syndrome, and carcinoid of the lung.
Use of cerebrospinal fluid reactivity with live hippocampal neurons is described as part of differentiation in the disclosure.
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