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-11242378-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 document describes human, pan-ebolavirus cross-reactive monoclonal antibodies and affinity-matured variants that bind Ebola virus glycoprotein (GP). The antibodies include specified heavy chain variable region sequences and specified light chain variable region sequences with defined heavy/light chain CDR1, CDR2, and CDR3 sequences. The binding antigen is Ebola glycoprotein, including cleaved GP species generated after GP→GPCL processing and receptor engagement.
The invention further defines the antibodies by glycoform characteristics, including glycoengineered variants that comprise predominantly a single glycoform. The predominantly single glycoform is specified to be selected from GnGn, G1/G2, and NaNa, and may substantially lack fucose and/or xylose. The document also describes monoclonal antibody combinations, including a cocktail comprising PE-87 and PE-47, for treatment of Ebola.
The document supports cross-reactivity across ebolavirus species with binding and neutralization/affinity data, including ELISA binding and in vitro neutralization/affinity measurements using VSV-GP and authentic virus. Structural and epitope mapping is described using EM reconstructions and GPCL binding site information. Virus escape studies identify GP substitutions, and efficacy is reported in multiple animal models including mice, guinea pigs, ferrets, and non-human primates with survival benefits and reduced viral RNA in treated primates.
Claims Coverage
The provided claim set includes two independent claims. Each centers on Ebola treatment using specified affinity-matured monoclonal antibodies or antigen-binding fragments that bind Ebola glycoprotein, defined by at-least-90% identical heavy/light variable regions and specific CDR sequences, with Claim 1 additionally covering a combination composition framework and Claim 7 requiring a predominantly single glycoform that binds at least two Ebola species.
Ebola treatment composition with defined affinity-matured variable regions and CDRs
A composition for the treatment of Ebola comprising a therapeutically effective combination of (i) a first monoclonal antibody or antigen binding fragment thereof having a heavy chain variable region at least 90% identical to SEQ ID NO: 15 and a light chain variable region at least 90% identical to SEQ ID NO: 18, each including affinity matured variants, and with specified heavy and light chain CDR1, CDR2, and CDR3 sequences (SEQ ID NO: 41–46), wherein the antibody binds Ebola glycoprotein, and (ii) a pharmaceutically acceptable excipient or carrier.
Monoclonal antibody or fragment with predominant single glycoform for Ebola treatment
A monoclonal antibody or antigen binding fragment thereof effective to treat Ebola comprising a heavy chain variable region at least 90% identical to SEQ ID NO: 15 and a light chain variable region at least 90% identical to SEQ ID NO: 18, each including affinity matured variants, and with specified heavy and light chain CDR1, CDR2, and CDR3 sequences (SEQ ID NO: 41–46), wherein the monoclonal antibody or antigen binding fragment comprises predominantly a single glycoform that binds at least two species of Ebola, and the antigen is Ebola glycoprotein.
Overall, the independent claims center on Ebola treatment using specified affinity-matured monoclonal antibodies or antigen-binding fragments that bind Ebola glycoprotein, defined by at-least-90% identical heavy/light variable regions and specific CDR sequences, with Claim 1 additionally covering a combination composition framework and Claim 7 requiring a predominantly single glycoform that binds at least two Ebola species.
Stated Advantages
Survival benefits in treated non-human primates.
Reduced viral RNA in treated primates.
Documented Applications
A composition for the treatment of Ebola.
A monoclonal antibody or antigen binding fragment effective to treat Ebola.
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