Monoclonal antibodies and cocktails for treatment of Ebola infections
Inventors
Bornholdt, Zachary A. • Zeitlin, Larry • Chandran, Kartik • Wec, Anna • Walker, Laura
Assignees
Albert Einstein College of Medicine • Adimab LLC • Mapp Biopharmaceutical Inc
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Publication Number
US-11407816-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 that cross-react across multiple ebolavirus species by binding Ebola glycoprotein, including cleaved GP species generated in endosomes. The document describes specific human monoclonal antibodies and affinity-matured variants that retain binding to Ebola glycoprotein and are characterized by defined antibody CDR regions. The invention also describes glycoprotein-antibody binding where the antigen comprises Ebola glycoprotein, including GP_CL.
The invention further addresses affinity-matured antibody variants and defines antibody specificity through provided CDR sequence information on heavy and light chains. In addition, it describes antibody glycoform engineering to produce predominantly single glycoforms, including glycoforms engineered to reduce or remove fucose and/or xylose. The disclosed glycoform characteristics are linked to antibodies comprising predominantly single glycoforms that bind Ebola glycoprotein across multiple species of ebolavirus.
The document describes functional outcomes including in vitro cross-reactivity and neutralization and strong post-exposure protection across multiple animal models, including mice, guinea pigs, ferrets, and non-human primates. It also reports escape mutant resistance patterns between cocktail components and states that combination therapy reduces the risk of resistance. Overall, the invention is directed to therapeutic compositions that combine antibody components targeting Ebola glycoprotein to treat Ebola infection with breadth across ebolavirus species.
Claims Coverage
The independent claims cover three inventive features: a therapeutically effective two-antibody composition, a method for treating multiple species of Ebola infection in a patient, and a therapeutic combination of at least two monoclonal antibodies effective to treat Ebola. Across these independents, the inventive features are defined by specific CDR sequence SEQ ID NOs and, in one claim set, by predominantly single glycoform characteristics.
Two Ebola glycoprotein-binding monoclonal antibodies with defined CDRs
A therapeutically effective combination for treating Ebola comprising a first monoclonal antibody or antigen binding fragment having heavy chain CDR1, CDR2, and CDR3 comprising SEQ ID NO: 53, 54, and 55 and light chain CDR1, CDR2, and CDR3 comprising SEQ ID NO: 56, 57, and 58, and a second monoclonal antibody or antigen binding fragment having heavy chain CDR1, CDR2, and CDR3 comprising SEQ ID NO: 41, 42, and 43 and light chain CDR1, CDR2, and CDR3 comprising SEQ ID NO: 44, 45, and 46, together with a pharmaceutically acceptable excipient or carrier.
Patient treatment with a therapeutically effective two-antibody Ebola glycoprotein composition
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 the two monoclonal antibodies or antigen binding fragments with the defined CDR SEQ ID NOs, plus a pharmaceutically acceptable excipient or carrier.
Therapeutic combination using predominantly single glycoform antibodies binding at least two Ebola glycoprotein species
A therapeutic combination of at least two monoclonal antibodies or antigen binding fragments effective to treat Ebola comprising the two monoclonal antibodies with the defined CDR SEQ ID NOs, wherein the first and second monoclonal antibodies or antigen binding fragments comprise predominantly single glycoforms that bind at least two species of Ebola glycoprotein.
Across the independent claims, the scope is anchored on two defined human monoclonal antibodies with specified CDRs that bind Ebola glycoprotein for therapeutic use. The claims also include a treatment method in a patient and a therapeutic combination framework, with one independent claim further centering the antibodies’ predominantly single glycoform composition.
Stated Advantages
Strong post-exposure protection across multiple animal models, including mice, guinea pigs, ferrets, and non-human primates.
In vitro cross-reactivity and neutralization across multiple ebolavirus species by binding Ebola glycoprotein, including cleaved GP species.
Combination therapy reduces the risk of resistance to escape mutants between cocktail components.
Documented Applications
Treating Ebola using a therapeutically effective combination of first and second monoclonal antibodies or antigen binding fragments that bind Ebola glycoprotein.
Treating multiple species of Ebola infection in a patient by identifying the patient and administering a therapeutically effective amount of the two-antibody composition.
Therapeutic combination use of at least two monoclonal antibodies or antigen binding fragments effective to treat Ebola.
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