Monoclonal antibodies and cocktails for treatment of Ebola infections
Inventors
Bornholdt, Zachary A. • Zeitlin, Larry • Chandran, Kartik • Wec, Anna Z. • Walker, Laura
Assignees
Albert Einstein College of Medicine • Adimab LLC • Mapp Biopharmaceutical Inc
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Publication Number
US-11407817-B2
Publication Date
2022-08-09
Expiration Date
Abstract
Described herein are compositions and methods for the prevention and treatment of ebolavirus infection. In certain embodiments of the present invention, monoclonal antibodies substantially similar to those described herein, as well as affinity matured variants thereof, alone or in combination, provide therapeutic efficacy in a patient against multiple species of ebolavirus.
Core Innovation
The invention relates to human pan-ebolavirus monoclonal antibodies and antibody cocktails that neutralize multiple Ebolaviruses by binding Ebola glycoprotein (GP), including cleaved GP (GPCL) forms in the endosome. The disclosure presents pan-species cross-reactivity as a key theme, supported by sequence-defined antibody variants and defined binding specificity for Ebola GP.
The disclosure provides antibody sequence-defined variants defined by VH/VL variable regions and CDRs with SEQ ID references. It also includes glycoengineered variants characterized as predominantly single glycoform variants, including GnGn, G1/G2, and NaNa, with reduced fucose and xylose, as well as affinity-matured variants.
The description reports neutralization and binding evidence, and in vivo efficacy across multiple lethal challenge models including mice, interferon-receptor-deficient mice, guinea pigs, ferrets, rhesus macaques, and cynomolgus macaques. It also reports enhanced protection by afucosylated or low-fucose cocktails and explores escape mutants with observed cross-enhancement effects that mitigate resistance risk, including mutations such as PE-87 G528E and PE-47 N514D.
Claims Coverage
The document includes three independent claims. Across these independent claims, the inventive coverage centers on a therapeutically effective combination of two monoclonal antibodies or antigen-binding fragments defined by specific CDR sequence identifiers, binding Ebola glycoprotein, and in one claim further characterized by predominantly single glycoforms that bind at least two Ebola glycoprotein species.
Ebola treatment composition with specified first and second antibody CDR sequences
A composition for treating Ebola comprising a therapeutically effective combination of a first monoclonal antibody or antigen-binding fragment with specified heavy- and light-chain CDRs defined by SEQ ID NOs 53-58, where the antigen comprises Ebola glycoprotein, and a second monoclonal antibody or antigen-binding fragment with specified heavy- and light-chain CDRs defined by SEQ ID NOs 47-52, where the antigen comprises Ebola glycoprotein, together with a pharmaceutically acceptable excipient or carrier.
Method for treating multiple species of Ebola infection using specified antibody combination
A method for treating multiple species of Ebola infection in a patient comprising identifying a patient in need of Ebola treatment and administering a therapeutically effective amount of a composition comprising a first monoclonal antibody or antigen-binding fragment with heavy- and light-chain CDRs defined by SEQ ID NOs 53-58 binding Ebola glycoprotein, a second monoclonal antibody or antigen-binding fragment with heavy- and light-chain CDRs defined by SEQ ID NOs 47-52 binding Ebola glycoprotein, and a pharmaceutically acceptable excipient or carrier.
Therapeutic combination of at least two antibodies with predominantly single glycoforms binding multiple Ebola species
A therapeutic combination of at least two monoclonal antibodies or antigen-binding fragments effective to treat Ebola comprising a first antibody or antigen-binding fragment with heavy- and light-chain CDRs defined by SEQ ID NOs 53-58 binding Ebola glycoprotein and a second antibody or antigen-binding fragment with heavy- and light-chain CDRs defined by SEQ ID NOs 47-52 binding Ebola glycoprotein, wherein the first and second monoclonal antibodies or antigen-binding fragments comprise predominantly single glycoforms that bind at least two species of Ebola glycoprotein.
All independent claims require two specified monoclonal antibodies or antigen-binding fragments defined by CDR sequence SEQ ID identifiers that bind Ebola glycoprotein, with one therapeutic combination claim additionally requiring predominantly single glycoforms that bind at least two Ebola glycoprotein species.
Stated Advantages
Neutralization of multiple Ebola species by pan-species cross-reactive antibodies binding Ebola glycoprotein.
Enhanced protection reported for afucosylated or low-fucose antibody cocktails.
Escape mutants with observed cross-enhancement effects, mitigating resistance risk.
Documented Applications
Treating Ebola using a therapeutically effective combination of specified monoclonal antibodies or antigen-binding fragments with pharmaceutically acceptable excipients.
Treating multiple species of Ebola infection in a patient by administering a therapeutically effective amount of a composition comprising the specified two monoclonal antibodies or antigen-binding fragments and a pharmaceutically acceptable excipient or carrier.
Therapeutic combination therapy effective to treat Ebola using at least two monoclonal antibodies or antigen-binding fragments comprising predominantly single glycoforms binding at least two species of Ebola glycoprotein.
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