Beta-lactamases with improved properties for therapy
Inventors
Kaleko, Michael • Connelly, Sheila
Assignees
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Publication Number
US-11236319-B2
Publication Date
2022-02-01
Expiration Date
Abstract
This invention relates to, in part, compositions of beta-lactamases and methods of using these enzymes in, for example, gastrointestinal tract (GI tract) disorders such as C. difficile infection (CDI).
Core Innovation
The disclosure relates to beta-lactamase therapeutics derived from P1A (Bacillus licheniformis PenP) comprising an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and mutations at Ambler classification positions 232, 237, 238, and 240. The engineered beta-lactamases broaden antibiotic substrate hydrolysis to penicillins and cephalosporins and are described with improved enzyme kinetics, including lower Km and higher Vmax and catalytic efficiency.
The engineered beta-lactamases are configured for use in the gastrointestinal (GI) tract during antibiotic therapy, with stability and limited activity loss across GI regions, resistance to proteases and beta-lactamase inhibitors, and activity across a pH range in the GI tract. The disclosure also describes oral and enteric delivery, including delayed-release behavior, and contemplated dosage forms such as tablets, multi-particulate sprinkle, and multi-particulate capsule formats.
The beta-lactamases are linked to prevention and/or treatment of C. difficile infection (CDI) and other antibiotic-associated GI adverse effects such as antibiotic-associated diarrhea (AAD) and C. difficile-associated disease. The disclosure also discusses co-therapy and adjuvants for CDI, including additional beta-lactamases or inhibitor-insensitive classes and agents such as metronidazole, vancomycin, fidaxomicin, rifaximin, probiotics, binders, and antibodies.
Claims Coverage
The partial content identifies two independent claims. Across these claims, the coverage centers on an engineered beta-lactamase defined by high sequence identity to SEQ ID NO: 1 with Ambler-position mutations and a method of preventing an antibiotic-induced GI adverse effect by administering that beta-lactamase.
Beta-lactamase with Ambler-position mutations and SEQ ID NO: 1 identity
A beta-lactamase comprising an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and mutations at Ambler classification positions 232, 237, 238, and 240.
Prevention of antibiotic-induced GI adverse effects by administering the engineered beta-lactamase
A method for preventing an antibiotic-induced adverse effect in the gastrointestinal tract, comprising administering an effective amount of a beta-lactamase to a patient in need thereof, wherein the beta-lactamase comprises an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and mutations at Ambler classification positions 232, 237, 238, and 240.
The independent claim set provides coverage for a specified engineered beta-lactamase defined by at least 98% sequence identity to SEQ ID NO: 1 plus Ambler-position mutations, and for using that enzyme in an effective amount to prevent antibiotic-induced GI adverse effects.
Stated Advantages
Broadens antibiotic substrate hydrolysis to penicillins and cephalosporins.
Improves enzyme kinetics, including lower Km and higher Vmax and catalytic efficiency.
Stability and limited activity loss across GI regions.
Resistance to proteases and beta-lactamase inhibitors.
Targeting the small and/or large intestine while limiting gastric fluid release.
Provides protection in the GI tract during antibiotic therapy.
Prevents and/or treats C. difficile infection (CDI) and other antibiotic-associated GI adverse effects such as antibiotic-associated diarrhea (AAD) and C. difficile-associated disease.
Documented Applications
Use in the gastrointestinal tract.
Oral administration embodiments, including tablet and multi-particulate sprinkle or multi-particulate capsule formats.
Prevention of an antibiotic-induced adverse effect in the GI tract by administering the described beta-lactamase to a patient.
Prevention (and/or treatment, as described) of C. difficile infection (CDI) and other antibiotic-associated GI adverse effects, including antibiotic-associated diarrhea (AAD) and C. difficile-associated disease.
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