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AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsStephen H. Leppla, Mary Jo Rosovitz, S. Dana Hsu
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The invention relates to improved methods of producing and recovering sporulation-deficient B. anthracis mutant stains, and for producing and recovering recombinant B. anthracis protective antigen (PA), especially modified PA which is protease resistant, and to methods of using of these PAs or nucleic acids encoding these PAs for eliciting an immunogenic response in humans, including responses which provide protection against, or reduce the severity of, B. anthracis bacterial infections and which are useful to prevent and/or treat illnesses caused by B. anthracis, such as inhalation anthrax, cutaneous anthrax and gastrointestinal anthrax.
A method of producing of B. anthracis protective antigen comprising culturing a cell or microorganism comprising a nucleotide sequence encoding said B. anthracis protective antigen in a manner to cause expression of said protective antigen wherein the culture medium is maintained at about pH 7 to about pH 8 substantially throughout the fermentation process.
A B. anthracis protective antigen wherein the amino acid sequence RKKR167 has been changed to SNKE167, the two phenylalanines at positions 313-314 are deleted and the glutamic acid at position 308 is substituted with aspartic acid.
An artificial nucleic acid construct encoding a B. anthracis PA wherein the amino acid sequence RKKR167 has been changed to SNKE167, the two phenylalanines at positions 313-314 are deleted and the glutamic acid at position 308 is substituted with aspartic acid.
A method for generating and isolating a sporulation-deficient bacterial mutant from a population of bacteria comprising the steps of:
A recombinant Bacillus anthrax protective antigen (PA) protein modified to incorporate one or more mutations comprising an amino acid deletion or substitution in a flexible, exposed, or loop segment of said PA protein selected from residues 162-174, 304-319, 1-13, 99-162, and 512-515 shown in FIGS. 7 and 8, said one or more mutations conferring enhanced resistance to protolytic degradation compared to wild type PA.
Dependencies are inferred from the claim text.