Potent zika virus-specific and cross-neutralizing monoclonal antibodies to zika and dengue viruses following ZIKV infection or vaccination
Inventors
Krebs, Shelly • Donofrio, Gina • Dussupt, Vincent • Modjarrad, Kayvon • BAROUCH, Dan • Jarman, III, Richard G. • MICHAEL, Nelson L. • Joyce, Gordon • Sankhala, Rajeshwer Singh • Stephenson, Kathryn Elaine
Assignees
Beth Israeli Deaconess Medical Center Inc • Beth Israel Deaconess Medical Center Inc • Henry M Jackson Foundation for Advancedment of Military Medicine Inc • United States Department of the Army
Publication Number
US-11884718-B2
Publication Date
2024-01-30
Expiration Date
2039-04-24
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Abstract
The invention described herein provides antibodies to Zika virus. The novel polypeptides are useful alone or as portions of larger molecules, such as antibodies or antibody fragments, that can be used to treat or prevent infection of Zika virus.
Core Innovation
The invention provides antibodies to Zika virus including novel polypeptides useful alone or as parts of larger molecules, such as antibodies or antibody fragments, for treating or preventing Zika virus infection. It addresses the need for neutralizing monoclonal antibodies (mAbs) specific to Zika virus, which can inform development of therapies and vaccines.
The background highlights that Zika virus (ZIKV) caused significant disease worldwide and is linked to serious complications such as microcephaly and Guillain-Barre syndrome. However, little was known about antibodies targeting ZIKV envelope (E) glycoprotein in flavivirus-naïve individuals. The invention accordingly seeks to understand and characterize ZIKV-specific neutralizing antibodies and their epitopes, including in individuals without prior flavivirus exposure, to improve vaccine design and therapeutics.
The invention involves the isolation and characterization of potent ZIKV-specific and cross-neutralizing monoclonal antibodies from non-human primates infected with ZIKV or human subjects vaccinated with ZIKV purified inactivated vaccine (ZPIV). These antibodies target distinct quaternary and conformational epitopes on the viral envelope, including a newly described E Tetramer Epitope (ETE), with demonstrated therapeutic potential. Additionally, the invention includes novel peptides, antibodies, antibody fragments, and nucleic acids encoding them, methods of isolating such antibodies, and their use in inhibiting ZIKV infection, treatment, prevention, diagnosis, and in pharmaceutical compositions.
Claims Coverage
The independent claims cover antibodies or antibody fragments that selectively bind Zika virus characterized by specific complementarity determining regions (CDRs), as well as methods and compositions involving these antibodies.
Antibodies with defined heavy and light chain CDR sequences that selectively bind Zika virus
Antibodies or fragments comprising heavy chain variable regions with specific CDR1, CDR2 and CDR3 amino acid sequences selected from SEQ ID NOs: 5-7, 15-17, 25-27, 35-37, 45-47, 55-57, 65-67, 75-77, 85-87, 95-97, 105-107, 115-117, 125-127, 135-137, 145-147, 155-157, 165-167, 175-177, 185-187, 195-197, 205-207, 215-217, and light chain variable regions with CDRs selected from SEQ ID NOs: 8-10, 18-20, 28-30, 38-40, 48-50, 58-60, 68-70, 78-80, 88-90, 98-100, 108-110, 118-120, 128-130, 138-140, 148-150, 158-160, 168-170, 178-180, 188-190, 198-200, 208-210, 218-220, wherein the antibody selectively binds Zika virus.
Antibodies or fragments that inhibit Zika virus infection or transmission
Antibodies or fragments capable of inhibiting or preventing Zika virus infection, Dengue virus infection including serotype 2 and 3, transmission from pregnant female to fetus, sexual transmission, or infection of human testes.
Antibodies with defined neutralization potency and specificity profiles
Antibodies or fragments having ED50 for neutralizing Zika infection less than 10 mg/kg, IC50 for neutralization less than 10 μM, and absence of neutralization of other flaviviruses such as Dengue virus, Japanese Encephalitis virus, West Nile virus, or Yellow Fever virus at 100 μg/ml concentration, and equilibrium dissociation constant (KD) in the range of 10−7 to 10−9 molar or less.
Use of antibody fragments and humanized antibodies
Antibody fragments such as Fab fragments, single chain variable fragments (scFv), humanized antibodies or humanized antibody fragments comprising the specified CDR sequences.
Nucleic acids and host cells encoding said antibodies
Polynucleotides comprising nucleotide sequences encoding the antibodies or fragments described and host cells comprising said polynucleotides.
Pharmaceutical compositions comprising these antibodies and related therapeutic methods
Pharmaceutical compositions including pharmaceutically acceptable carriers and the specified antibodies or antibody fragments for prevention or treatment of flavivirus infections and methods of administering them for treatment, prevention, or inhibition of transmission including from pregnant females to fetus and sexual transmission.
Diagnostic and detection methods and kits using these antibodies
Methods for detecting presence of flavivirus in biological samples by contacting with said antibodies and detecting binding, methods of diagnosing infection, detecting latent infection, measuring vaccine efficacy, and kits comprising these antibodies for detection.
Antibodies targeting specific epitopes of Zika virus E glycoprotein
Antibodies or fragments that bind the DI-DIII linker domain of Zika virus E glycoprotein and exhibit neutralization activity influenced by substitution at residue Tyrosine 305.
Method of isolating antibodies binding cross-protomer virus epitopes
A method involving immunizing a subject with viral immunogen, isolating PBMCs, contacting PBMCs with intact virus, fluorescent labeling, isolating fluorescent PBMCs, isolating polynucleotides encoding heavy and light chains from these PBMCs, expressing the polynucleotides in host cells, and isolating the expressed antibody.
Multispecific antibodies binding different flavivirus epitopes
Multispecific antibodies comprising multiple binding sites targeting different flavivirus epitopes, including multiple binding sites combined via knob-in-hole mutations and single-chain variable fragment insertions, with specific binding and neutralization profiles against Zika virus and Dengue virus.
The claims cover a broad range of antibodies and antibody fragments with specific CDR sequences selectively binding Zika virus, exhibiting potent neutralizing capacity, including cross-neutralization with Dengue virus, methods of production, pharmaceutical compositions, therapeutic and diagnostic uses, methods for antibody isolation, and multispecific antibody constructs designed for enhanced flavivirus neutralization.
Stated Advantages
Potent ZIKV-specific and cross-neutralizing antibodies can be generated during acute infection without pre-existing flavivirus immunity, with broad implications for vaccine design.
The isolated antibodies demonstrate therapeutic potential with distinct modes of recognition targeting the viral envelope.
Vaccination in Dengue-experienced individuals elicits rapid, potent neutralizing responses boosting pre-existing cross-neutralizing immunity.
High potency neutralizing antibodies protect mice fully against Zika virus infection at low doses.
Multispecific antibodies targeting multiple epitopes increase protective potential and neutralization breadth against multiple flaviviruses.
Documented Applications
Treatment and prevention of Zika virus infection using antibodies or antibody fragments that selectively bind Zika virus.
Prophylaxis against flavivirus infections including Zika virus, Dengue virus serotypes 2 and 3, West Nile virus, and Japanese Encephalitis virus.
Inhibition or prevention of transmission of Zika virus from pregnant female to fetus and sexual transmission of Zika virus infection.
Diagnostic methods and kits for detecting presence of flavivirus or Zika virus in biological samples.
Measurement of efficacy of flavivirus vaccine batches using binding of the described antibodies.
Purification of flavivirus E glycoprotein by using antibodies or antibody fragments.
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