Antibodies against chikungunya virus and uses thereof
Inventors
Doranz, Benjamin • Mattia, Kimberly-Anne • Kahle, Kristen • Simmons, Graham • Fong, Rachel Hua-Ning • Banerjee, Soma Banik
Assignees
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Publication Number
US-9902765-B2
Publication Date
2018-02-27
Expiration Date
Abstract
Embodiments disclosed herein provide for antibodies, including neutralizing antibodies, against Chikungunya virus, uses thereof, and methods of identifying antibodies, including neutralizing antibodies, against Chikungunya virus. In some embodiments, antibodies that binds to a CHIKV antigen, wherein the antigen is the CHIKV E1, E2, E3 protein, or any heterocomplex thereof are provided. In some embodiments, the antibody is an isolated antibody, a neutralizing antibody, a recombinant antibody, or any combination thereof. In some embodiments, the antibodies described herein bind to an epitope of E2 Domain A, E2 Domain B, or E1 Domain II of the CHIKV antigen. In some embodiments, the antigen is E2 protein.
Core Innovation
The invention relates to recombinant or neutralizing anti-CHIKV antibodies that target structural envelope proteins of Chikungunya virus (CHIKV), including E1, E2, and E3, and including E1/E2 heterocomplexes. The antibodies are described in terms of their epitope specificity mapped to CHIKV E2 domains A and B and E1 domain II, and the document describes isolating and characterizing human CHIKV-specific monoclonal antibodies from infected patients using phage-display/FAb libraries.
The epitope mapping is supported by identification of critical residue sets within CHIKV envelope protein regions, including E2-A162, E2-A residues Y69/F84/V113/G114/T116/D117, and residue combinations including G95, A164/E165/E166/I167, and subunit/residue combinations on E2 and E1. Antibodies are further described using residue/epitope fragment targeting where antigen specificity is linked to CHIKV E2 and E1 epitope regions, and the document maps antibody epitopes on CHIKV E2/E1 by comprehensive alanine-scanning (“shotgun mutagenesis”).
The invention also describes antibody formats and applications, including isolated antibodies and recombinant antibodies, and antibody formats such as human and humanized forms and antigen-binding fragments. The disclosed use cases include therapeutic and prophylactic treatment and antigen detection, and the document includes examples where antibody properties and immune response induction are associated with antigen or epitope fragments.
Claims Coverage
The independent claim defines a recombinant antibody by two specific amino acid sequences, and the dependent claims refine the same antibody to compositions with formulation components. Coverage centers on one inventive feature with composition refinements.
Recombinant antibody defined by two specified amino acid sequences
A recombinant antibody comprising a first amino acid sequence comprising the amino acid sequence of SEQ ID NO: 13 and a second amino acid sequence comprising the amino acid sequence of SEQ ID NO: 14.
Antibody in a buffer-containing composition
The antibody of claim 1 in a composition that includes a buffer.
Pharmaceutical composition with pharmaceutically acceptable excipient
The composition of claim 2 further including a pharmaceutically acceptable excipient.
Across the claim set provided, coverage is centered on the recombinant antibody defined by SEQ ID NO: 13 and SEQ ID NO: 14, with further scope limited to specific composition contexts that include a buffer and a pharmaceutically acceptable excipient.
Stated Advantages
Potent neutralizing and conformational activity for CAP4A-E7 with low IC50 and PRNT50 values.
Therapeutic efficacy reported up to 24 hours post-infection in neonatal lethality and adult arthritis mouse models.
Epitope location insights linking neutralizing epitopes on the outer/top of the E2/E1 trimer to higher potency, and non-neutralizing interior or occluded regions to limited activity.
Documented Applications
Using phage-display/FAb libraries to isolate and characterize CHIKV-specific monoclonal antibodies from infected patients.
Mapping antibody epitopes on CHIKV E2/E1 by comprehensive alanine-scanning (“shotgun mutagenesis”).
Evaluating neutralization and binding using neutralization assays including PRNT and pseudovirus neutralization, and binding kinetics by biolayer interferometry (Octet).
Testing therapeutic efficacy in a neonatal lethality mouse model and an adult arthritis mouse model, with reported efficacy up to 24 hours post-infection.
Therapeutic and prophylactic treatment.
Antigen detection.
Antibody identification and immune response induction via antigen/epitope fragments.
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