Human monoclonal antibody with specificity for dengue virus serotype 1 E protein and uses thereof
Inventors
Macary, Paul Anthony • Teoh, Ee Ping Evelyn • Hanson, Brendon John • Teo, En Wei • Lim, Angeline Pei Chiew • Ng, Mah Lee Mary • Lok, Shee Mei • Kukkaro, Petra Eveliina
Assignees
National University of Singapore • DSO National Laboratories
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Publication Number
US-10294293-B2
Publication Date
2019-05-21
Expiration Date
Abstract
Compositions and methods for the treatment or prevention of Dengue virus infection in a vertebrate subject are provided. In particular, human neutralizing monoclonal antibodies to Dengue virus isolated from EBV immortalized B cells derived from patients who have recovered from Dengue infection are disclosed. Methods are provided for administering such antibodies to a vertebrate subject in an amount effective to reduce, eliminate, or prevent relapse from infection.
Core Innovation
The invention relates to fully human neutralizing monoclonal antibodies against Dengue virus serotype 1 envelope (E) protein. The antibodies are generated from EBV-immortalized CD22+ memory B cells derived from convalescent patients and specifically bind to the Dengue virus serotype 1 E protein with broadly neutralizing activity.
A central feature is binding across two E proteins in a virus through a quaternary-structure epitope. The binding across two E proteins comprises binding to DI and the hinge between DI and II on one E protein and DIII of a neighboring E protein, with the interaction associated with specified amino acids in DI, DII, and DIII.
The document further describes antibody HM14c10/14c10.8 with serotype-1 specificity, neutralization, and binding across two E proteins, together with mechanistic and phenotypic characterization including in vitro and in vivo performance and ADE behavior. It includes related antibody forms, nucleic acids/expression, and pharmaceutical compositions, optionally combined with a second agent, and describes prophylactic and therapeutic use via passive immunization in vertebrate subjects.
Claims Coverage
The independent claims cover methods of passive immunization and treatment of Dengue virus infection using isolated human neutralizing monoclonal antibodies with broadly neutralizing activity across two E proteins, defined epitope binding across E protein domains and hinge, and specified antibody heavy-chain and light-chain CDR sequences or specified SEQ ID heavy and light chain sequences. Four independent method claims are presented.
Passive immunization with human broadly neutralizing antibody binding across two E proteins
Administration to a subject of an effective amount of an isolated neutralizing monoclonal antibody that specifically binds to a Dengue virus serotype 1 envelope (E) protein, where the antibody is a human antibody with broadly neutralizing activity that binds across two E proteins in a virus and binds to DI and the hinge between DI and II on one E protein and DIII of a neighboring E protein.
Treating Dengue virus infection with neutralizing human antibody effective to reduce or prevent infection
Administration to a subject of an amount of an isolated neutralizing monoclonal antibody that specifically binds to a Dengue virus serotype 1 envelope (E) protein and is effective to reduce or prevent the Dengue virus infection, where the antibody is a human antibody with neutralizing activity that binds across two E proteins and binds to DI and the hinge between DI and II on one E protein and DIII of a neighboring E protein.
Treating Dengue virus serotype 1 infection using antibody with specified CDR sequences
Administration to a subject of an amount of an isolated antibody effective to reduce or prevent the Dengue virus infection, where the antibody comprises heavy chain CDR sequences SYGMH, VIWYDGSKTYYGDSVKG, and GIAGGWAFW, and light chain CDR sequences RASQNVYSYLG, GVTSRAT, and QQYAG.
Treating Dengue virus serotype 1 infection using antibody defined by SEQ ID heavy and light sequences
Administration to a subject of an amount of an isolated antibody effective to reduce or prevent the Dengue virus infection, where the antibody comprises a heavy chain sequence comprising SEQ ID NO:20 and a light chain sequence comprising SEQ ID NO:27.
Across the independent claims, the inventive concept is administration of an isolated human neutralizing monoclonal antibody for passive immunization or treatment of Dengue virus infection, with broadly neutralizing or neutralizing activity tied to binding across two E proteins via DI and the hinge region on one E protein and DIII on a neighboring E protein, and with antibody identity defined by specified CDR sequences or specified SEQ ID heavy and light chain sequences.
Stated Advantages
Broadly neutralizing activity binding across two E proteins in a virus.
Neutralizing activity effective to reduce or prevent Dengue virus infection.
Documented Applications
Prophylactic and therapeutic use via passive immunization in vertebrate subjects for Dengue virus serotype 1 infection and Dengue virus infection.
Reduction or prevention of Dengue virus infection following administration of the isolated antibody.
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