Measurement of afucosylated igg fc glycans and related treatment methods

Patent metadata

Field	Value
Publication number	US-2020261564-A1
Application number	US-201816758364-A
Country	US
Kind code	A1
Filing date	Oct 22, 2018
Priority date	Oct 23, 2017
Publication date	Aug 20, 2020
Grant date	—

Abstract

The present disclosure provides methods related to determining the level of afucosylated Fc glycans in IgG antibodies in a biological sample from a subject. This level can be used in methods aimed at monitoring and/or treating subject suffering from an acute flavivirus infection and/or who are at risk for progression to clinically significant infection or disease. This level can also be used in a vaccination method to ensure that those who receive a flavivirus vaccine have a reduced risk of reacting to the vaccine be developing clinically significant infection or disease. The disclosure also provides treatment methods based on inhibiting FcγRIIA or FcγRIIIA receptor signaling. Also provided are novel cell lines that are useful in measuring afucosylated Fc glycans.

First claim

1 . A vaccination method, the method comprising vaccinating a subject against a flavivirus if the subject has been determined not to have an elevated level of afucosylated Fc glycans in IgG antibodies in a biological sample from the subject or, in an infant subject, if the mother of the infant, has been determined not to have an elevated level of afucosylated Fc glycans in IgG antibodies in a biological sample from the mother.

2 . The vaccination method of claim 1 , wherein the IgG antibodies are IgG1 antibodies.

3 . (canceled)

4 . The vaccination method of any one of claim 1 , wherein the IgG antibodies are IgG antibodies specific for a flaviviral antigen.

5 . The vaccination method of claim 4 , wherein the flaviviral antigen is a dengue viral antigen or a Zika viral antigen.

6 - 7 . (canceled)

8 . The vaccination method of claim 1 , wherein the elevated level of afucosylated Fc glycans is defined as 10 percent or greater.

9 . (canceled)

10 . The vaccination method of claim 1 , wherein the subject is an infant, wherein the mother of the infant has IgG antibodies that are reactive with the flavivirus.

11 - 12 . (canceled)

13 . A method of treating a subject acutely infected with a flavivirus and at risk of progression to clinically significant flaviviral infection or disease, the method comprising administering to the subject one or more inhibitors selected from the following:
an inhibitor of FcγRIIA receptor signaling; an inhibitor of FcγRIIIA receptor signaling; an inhibitor of FcγRI receptor signaling; and an inhibitor of immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling.

14 - 15 . (canceled)

16 . The method of claim 13 , wherein the i) inhibitor inhibits binding between the Fc region of IgG antibodies and the FcγRIIA, FcγRIIIA, or FcγRIIIA receptor and/or inhibits expression of the FcγRIIA, FcγRIIIA, or FcγRIIIA receptor.

17 . (canceled)

18 . The method of claim 13 , wherein the inhibitor inhibits FcγRIIA and FcγRIIIA receptor signaling, or the method comprises co-administering inhibitors of FcγRIIA and FcγRIIIA receptor signaling.

19 . The method of claim 13 , wherein the subject has tested positive for a flaviviral infection.

20 . The method of claim 13 , wherein the subject has been determined to have an elevated level of afucosylated Fc glycans by assaying a biological sample from the subject.

21 . The method of claim 13 , wherein the inhibitor comprises therapeutic IgGs or Fc regions thereof that have a higher level of fucosylated Fc regions than IgG in the biological sample from the subject.

22 . (canceled)

23 . The method of claim 20 , wherein the IgG antibodies are IgG1 antibodies.

24 . (canceled)

25 . The method of claim 20 , wherein the IgG antibodies are IgG antibodies specific for a flaviviral antigen.

26 . The method of claim 25 , wherein the flaviviral antigen is a dengue viral antigen or a Zika viral antigen.

27 - 28 . (canceled)

29 . The method of claim 20 , wherein the elevated level of afucosylated Fc glycans is defined as 10 percent or greater.

30 - 31 . (canceled)

32 . The method of claim 20 , wherein the subject has the acute flaviviral infection in the presence of preexisting IgG antibodies that are reactive with the infecting flavivirus.

33 . The method of claim 20 , wherein the subject is an infant who has a mother who has IgG antibodies that are reactive with the infecting flavivirus.

34 - 36 . (canceled)

37 . An assay method for determining a relative level of afucosylated antibodies, wherein the assay method comprises:
contacting a test sample, or antibodies derived therefrom,
with a cell line in the presence of a flavivirus,
wherein the cell line does not express a FcγRIIA receptor or does not express a FcγRIIIA receptor; and
measuring the level of infection or virus output, and determining the level of afucosylated antibodies relative to the level of infection or virus output measured when a known level of afucosylated antibodies is contacted with the cell line in the presence of the flavivirus.

38 . A pharmaceutical composition formulated for use in treatment of a subject acutely infected with a flavivirus according to the method of claim 13 , wherein said inhibitor comprises fucosylated IgG antibodies, or fucosylated Fc regions thereof, wherein greater than 95 percent of the IgG antibodies, or Fc regions thereof, are fucosylated.

39 - 43 . (canceled)

Assignees

• Chan Zuckerberg Biohub Inc
• The Board Of Trustees Of The Lelad Stanford Junior Univ

Inventors

• Wang Taia T

Classifications

• C07K16/116

  Togaviridae (F); Matonaviridae (F); Flaviviridae (F) · CPC title

• C07K16/108

  Orthomyxoviridae (F), e.g. influenza virus · CPC title

• A61K39/12 Primary

  Viral antigens · CPC title

• G01N33/56983

  Viruses · CPC title

• G01N2333/185

  Flaviviruses or Group B arboviruses, e.g. yellow fever virus, japanese encephalitis, tick-borne encephalitis, dengue · CPC title