Antibodies that bind B. anthracis exotoxin, formulations thereof, and methods of use
Inventors
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Publication Number
US-8093360-B2
Publication Date
2012-01-10
Expiration Date
Abstract
The present invention provides an antibody which binds to B. anthracis with toxin, formulations for administration of such antibodies intramuscularly, and methods of administering such antibodies prophylactically or therapeutically.
Core Innovation
The invention relates to anti–Bacillus anthracis protective antigen (PA) high-affinity neutralizing antibodies derived from murine 14B7. The antibodies are re-engineered and deimmunized into a human IgG1 format with defined complementarity determining regions (CDRs) and variable region framework regions.
Specific heavy chain variable region and light chain variable region definitions are provided using framework amino acid residues and CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 sequence sets (SEQ ID NOs). The disclosed antibodies exhibit binding affinity characterized by a Kd in a low-nanomolar range as supported by surface plasmon resonance.
The document describes that the antibody is combined with pharmaceutically acceptable carrier for intravenous or intramuscular administration. Use concepts include prophylactic and therapeutic administration and the potential for combination with antibiotics such as levofloxacin or ciprofloxacin, including timed post-exposure administration.
The disclosure further supports practical performance through preclinical and translational comparisons. Examples describe enhanced survival versus antibiotic alone in a rabbit spore challenge model, and pharmacokinetic/route comparability in non-human primates including cynomolgus monkeys, with reported IM bioavailability.
Claims Coverage
The document includes two independent claims. The claim set is grounded in defined antibody variable region architecture and covers pharmaceutical compositions for intravenous or intramuscular administration as well as isolated antibodies or binding molecules defined by specific SEQ ID NO sequences, with dependents refining Fc features and dosing-related formulation constraints.
Intravenous or intramuscular PA-binding antibody composition with defined variable-region framework and CDRs
A composition comprising an isolated antibody that binds protective antigen (PA) of B. anthracis and a pharmaceutically acceptable carrier, wherein the isolated antibody comprises a heavy chain variable region with framework amino acid residues set forth in SEQ ID NO:1 and CDRH1, CDRH2, and CDRH3; and a light chain variable region with framework amino acid residues set forth in SEQ ID NO:2 and CDRL1, CDRL2, and CDRL3, with each CDR defined by specified SEQ ID NOs.
Isolated PA-binding antibody with defined heavy- and light-chain variable region sequences
An isolated antibody comprising a light chain variable region and a heavy chain variable region, or a binding molecule comprising the light chain variable region and the heavy chain variable region thereof, wherein the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:2 and the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:1.
Overall, the claim coverage centers on a defined PA-binding antibody composition formulated for intravenous or intramuscular administration with heavy and light variable regions defined by specific framework residues and CDR sequences, and on isolated antibody or binding molecule formats defined directly by the specified light- and heavy-chain variable region sequences. Dependent claims further refine Fc features and add formulation and route restrictions.
Stated Advantages
Enhanced survival versus antibiotic alone in a rabbit spore challenge model.
Low-nanomolar binding affinity as characterized by Kd.
IM bioavailability and pharmacokinetic/route comparability in non-human primates.
Documented Applications
Prophylactic or therapeutic administration of an anti–B. anthracis PA neutralizing antibody composition formulated for intravenous or intramuscular administration.
Combination use with antibiotics such as levofloxacin or ciprofloxacin, including timed post-exposure administration.
Use evaluated in a rabbit spore challenge model for survival outcomes.
Pharmacokinetic/route evaluation in cynomolgus monkeys, including intramuscular bioavailability.
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