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-11242379-B2
Publication Date
2022-02-08
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 provides pan-ebolavirus human monoclonal antibodies and affinity-matured variants that neutralize multiple ebolavirus species by targeting Ebola glycoprotein (GP). The antibodies include a cleaved GP (GPCL) species generated after GP→GPCL cleavage in endosomes, and the invention specifies antibody binding to Ebola glycoprotein antigen.
The invention further characterizes antibody paratope features including heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3 sequence definitions. It also describes affinity-matured variants and antibody forms selected to exhibit pan-ebolavirus cross-reactivity and neutralization across Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), Reston virus (RESTV), and Tai Forest virus (TAFV).
The invention additionally describes glycoengineered antibody variants, including afucosylated and predominantly single-glycoform variants (e.g., GnGn, G1/G2, NaNa), and variants substantially lacking fucose and/or xylose. It describes use of antibody cocktails, including MBP134=PE-87+PE-47, and reports reduced viral escape when antibodies are combined.
Claims Coverage
The partial content identifies two independent claims. These claims focus on affinity-matured monoclonal antibodies or antigen binding fragments defined by heavy and light chain variable regions, specified CDR sequences, binding to Ebola glycoprotein, and predominantly single-glycoform binding at least two ebolavirus species.
Therapeutically effective Ebola treatment combination with defined affinity-matured antibody binding Ebola glycoprotein
A therapeutically effective combination for the treatment of Ebola comprising a first monoclonal antibody or antigen binding fragment thereof having heavy and light chain variable regions with at least 90% identical sequences to specified SEQ IDs, affinity matured variants, specified heavy and light chain CDR1/2/3 sequences, where the antibody binds Ebola glycoprotein, and a pharmaceutically acceptable excipient or carrier.
Monoclonal antibody effective to treat Ebola with defined CDR sequences, predominantly single glycoform binding at least two species
A monoclonal antibody or antigen binding fragment thereof effective to treat Ebola having heavy and light chain variable regions with at least 90% identical sequences to specified SEQ IDs, affinity matured variants, specified heavy and light chain CDR1/2/3 sequences, wherein the antibody comprises predominantly a single glycoform that binds at least two species of Ebola, and where the antigen comprises Ebola glycoprotein.
Across the independent claims, the inventive coverage is directed to specific affinity-matured monoclonal antibodies or antigen binding fragments defined by heavy and light chain variable region identity, specific CDR1/2/3 sequences, and binding to Ebola glycoprotein, with emphasis on predominantly single-glycoform antibodies binding at least two Ebola species and, for the composition claim, inclusion in a therapeutically effective combination with a pharmaceutically acceptable excipient or carrier.
Stated Advantages
Neutralize multiple ebolavirus species by targeting Ebola glycoprotein.
Provide pan-ebolavirus cross-reactivity and neutralization across EBOV, SUDV, BDBV, RESTV, and TAFV.
Reduce viral escape when antibodies are combined.
Improved efficacy for afucosylated cocktail variants and late post-exposure dosing (as documented in animal protection results).
Documented Applications
Treatment of Ebola using a therapeutically effective combination of affinity-matured monoclonal antibodies binding Ebola glycoprotein, together with a pharmaceutically acceptable excipient or carrier.
Monoclonal antibody administration effective to treat Ebola, including antibodies characterized by predominantly single glycoform binding at least two Ebola species.
Animal model protection documented in mice, guinea pigs, ferrets, and non-human primates (rhesus macaques and cynomolgus monkeys), including improved efficacy reported for afucosylated cocktail variants and late post-exposure dosing.
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