Autoantibodies as biomarker of paraneoplastic encephalitis associated with testicular cancer

Patent metadata

Field	Value
Publication number	US-2022196662-A1
Application number	US-202017439359-A
Country	US
Kind code	A1
Filing date	Mar 13, 2020
Priority date	Mar 15, 2019
Publication date	Jun 23, 2022
Grant date	—

Abstract

This disclosure describes methods and compositions for detecting the presence of a Kelch-like protein 11 autoantibody in a biological sample. Also provided are methods of treating subjects with testicular cancer or a premalignant condition and paraneoplastic encephalomyelitis.

First claim

1 . A method of detecting the presence of a Kelch-like protein 11 (KLHL11) autoantibody in a biological sample from a male subject presenting with encephalitis, comprising the steps of:
(a) contacting the biological sample with a KLHL11 polypeptide or antigenic fragment or variant thereof; and (b) detecting the presence of binding of the KLHL11 polypeptide or antigenic fragment or variant thereof to the KLHL11 autoantibody in the biological sample.

2 . The method of claim 1 , wherein the KLHL11 polypeptide or antigenic fragment or variant thereof is heterologously-expressed on the surface of a cell, a phage, or a virus.

3 . The method of claim 1 , wherein the KLHL11 polypeptide or antigenic fragment or variant thereof is expressed in a phage display or eukaryotic cell display library.

4 . The method of claim 1 , wherein the KLHL11 polypeptide or antigenic fragment or variant thereof is an isolated, purified KLHL11 polypeptide or fragment thereof.

5 . The method of claim 1 , wherein the KLHL11 polypeptide or antigenic fragment or variant thereof is an isolated, purified KLHL11 polypeptide or fragment thereof that is immobilized on a solid carrier.

6 . The method of claim 1 , wherein the KLHL11 polypeptide or antigenic fragment or variant thereof thereof comprises one or more of the sequences of SEQ ID NOs: 1-30.

7 . The method of claim 6 , wherein the KLHL11 polypeptide or antigenic fragment or variant thereof comprises the sequence of SEQ ID NO:4.

8 . The method of claim 1 , wherein the KLHL11 polypeptide or antigenic fragment or variant thereof is in brain tissue or other nervous tissue.

9 . The method of claim 1 , wherein the biological sample is serum, plasma, cerebrospinal fluid, blood, or urine.

10 . The method of claim 1 , wherein the male subject has one or more of ataxia, cognitive decline, mood disorder, hearing loss, tinnitus, trigeminal neuralgia, vertigo, diplopia, dysarthria, or other neurological deficit.

11 . The method of claim 1 , wherein the male subject has one or more of ataxia, hearing loss, tinnitus, or vertigo.

12 . The method of claim 1 , wherein the male subject has at least one of:
(i) a cerebrospinal fluid protein count of greater than 30 mg per deciliter; (ii) a cerebrospinal fluid blood cell count of at least 1 per cubic millimeter; (iii) two or more cerebrospinal oligoclonal bands; or (iv) a CSF index greater than 0.6.

13 . The method of claim 1 , wherein the male subject has at least one risk factor for testicular cancer.

14 . The method of claim 1 , wherein the male subject has not been previously diagnosed with testicular cancer.

15 . The method of claim 1 , wherein the male subject has been previously treated for testicular cancer or a premalignant condition or is being treated for testicular cancer or a premalignant condition.

16 . The method of claim 1 , wherein the presence of the binding of the KLHL11 polypeptide or antigenic fragment or variant thereof to said KLHL11 autoantibody in the biological sample indicates that the subject has or is at risk of having testicular cancer or a premalignant testicular condition.

17 . The method of claim 16 , wherein the testicular cancer is seminoma.

18 . The method of claim 1 , wherein the presence of the binding of the KLHL11 polypeptide or antigenic fragment or variant thereof to said KLHL11 autoantibody in the biological sample indicates that the subject has paraneoplastic encephalitis.

19 . The method of claim 16 , wherein the premalignant testicular condition is at least one of testicular microlithiasis, testicular atrophy, or testicular fibrosis.

20 . The method of claim 1 , wherein step (b) of detecting is performed by at least one of immunohistochemical staining, immunoprecipitation, microarray analysis, enzyme-linked immunosorbent assay (ELISA), or Western blot analysis.

21 . The method of claim 1 , wherein the KLHL11 polypeptide or fragment thereof is in a tissue section,
wherein step (a) comprises contacting the tissue section with the biological sample and a detectably-labeled secondary antibody under conditions in which a complex is formed between KLHL11 polypeptides in the tissue section, a corresponding KLHL11 autoantibody in the biological sample, if present, and the detectably-labeled secondary antibody, and wherein step (b) comprises identifying a pattern of complex formation in the tissue sample by detecting the detectably-labeled secondary antibody, wherein the presence of a pattern of complex formation is indicative of the presence of a KLHL11 autoantibody in the biological sample, and wherein the absence of a pattern of complex formation is indicative of the absence of a KLHL11 autoantibody in the biological sample.

22 . The method of claim 21 , wherein the pattern of complex formation in the brain tissue is sparse yet widespread throughout the brain, including the hippocampus, cerebral cortex, cerebellum, midbrain, and brain stem, and is enriched in perivascular tissue, perimeningeal tissue, and white matter tracts.

23 . The method of claim 1 , wherein the KLHL11 polypeptide or fragment thereof is heterologously-expressed on the surface of a cell,
wherein step (a) comprises contacting the cell heterologously-expresses the KLHL11 polypeptide or antigenic fragment or variant thereof on its surface with the biological sample and a detectably-labeled secondary antibody under conditions in which a complex is formed between KLHL11 polypeptides in the tissue section, a corresponding KLHL11 autoantibody in the biological sample, if present, and the detectably-labeled secondary antibody, and wherein step (b) comprises detecting the detectably-labeled secondary antibody, wherein detecting the presence of the detectably-labeled secondary antibody is indicative of the presence of a KLHL11 autoantibody in the biological sample, and wherein not detecting the presence of the detectably-labeled secondary antibody is indicative of the absence of a KLHL11 autoantibody in the biological sample.

24 . A method of treating a male subject having testicular cancer or a premalignant testicular condition and paraneoplastic encephalomyelitis, comprising the steps of:
(a) detecting the presence or absence of a Kelch-like protein 11 (KLHL11) autoantibody in a biological sample from a male subject presenting with rhomboencephalitis using the method of any of claims 1 - 23 , wherein detecting the KLHL11 autoantibody in the biological sample indicates that the subject has testicular cancer or a premalignant condition and paraneoplastic encephalomyelitis; (b) performing an examination of the male subject to determine the presence of testicular cancer or a premalignant testicular condition in the male subject; and (c) administering to the male subject an immunosuppressive therapy and, if the male subject has testicular cancer or a premalignant testicular condition, a treatment for testicular cancer or the premalignant testicular condition.

25 - 34 . (canceled)

Assignees

• Chan Zuckerberg Biohub Inc
• Univ California
• Mayo Found Medical Education & Res

Inventors

• Derisi Joseph L
• Wilson Michael R
• Mandel-Brehm Caleigh
• O'Donovan Brian
• Pittock Sean J
• Dubey Divyanshu
• Kryzer Thomas J
• Lennon Vanda A
• Mckeon Andrew

Classifications

• G01N33/57557 Primary

  of other specific parts of the body, e.g. brain · CPC title

• G01N33/564

  for pre-existing immune complex or autoimmune disease {, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9} · CPC title

• A61K38/45

  Transferases (2) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• G01N2800/28

  Neurological disorders · CPC title