Antibodies for the treatment of Clostridium difficile-associated infection and disease
Inventors
Ma, Dangshe • Nagashima, Kirsten • Kennedy, Brian • Donovan, Gerald P. • Kang, Yun • Olson, William C. • Kumar, Shankar • Tsurushita, Naoya • Marozsan, Andre J. • Cupo, Albert
Assignees
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Publication Number
US-8986697-B2
Publication Date
2015-03-24
Expiration Date
Abstract
Provided herein are reagents, compositions, and therapies with which to treat Clostridium difficile infection and related disease conditions and pathologies, such as Clostridium difficile-associated diarrhea, resulting from infection by Clostridium difficile bacteria and the enterotoxins produced by these bacteria. In particular, antibodies or antigen-binding fragments thereof that bind specifically to toxin A and/or toxin B of C difficile and neutralize the activities of these toxins; compositions comprising such antibodies; and methods of using the antibodies and the compositions are provided.
Core Innovation
The invention relates to isolated antibodies or antigen-binding fragments thereof that specifically bind Clostridioides difficile toxin A and/or toxin B. The antibodies include defined CDR1, CDR2, and CDR3 regions of the variable heavy chain and the variable light chain, associated with monoclonal antibodies produced by hybridoma cell lines deposited under ATCC accession numbers PTA-9692, PTA-9694, PTA-9888, and PTA-9693.
The invention further specifies alternative antibody embodiments in which the VH and VL CDRs correspond to particular SEQ ID NO sets or residue spans within the referenced SEQ ID NOs. In these embodiments, the antibody specifically binds toxin A of C. difficile or specifically binds toxin B of C. difficile through defined CDR compositions.
The patent also includes antibody formats that expand binding functionality, including bispecific antibody formats. The document describes neutralization of C. difficile toxin activity and addresses C. difficile infection and C. difficile-associated disease by providing toxin-targeting antibody compositions intended for treatment and prophylaxis, including recurrence, and by associating the antibodies with pharmaceutical compositions and kits for administration and delivery.
Claims Coverage
The independent claims cover isolated antibodies or antigen-binding fragments with defined binding specificity and defined VH/VL CDR compositions. Across the claims, the inventive features focus on specific binding to C. difficile toxin A and/or toxin B and defined CDR content derived from deposited hybridoma sources, SEQ ID NO CDR sets, or CDR residue spans.
Atcc-deposited cdr-defined toxin a or toxin b binder
An isolated antibody or an antigen-binding fragment thereof that specifically binds toxin A of C. difficile and comprises the CDR1, CDR2, and CDR3 of the VH and the CDR1, CDR2, and CDR3 of the VL of the monoclonal antibody produced by the hybridoma cell line deposited under ATCC Accession No. PTA-9692, PTA-9694, or PTA-9888; or specifically binds toxin B of C. difficile and comprises the CDR1, CDR2, and CDR3 of the VH and the CDR1, CDR2, and CDR3 of the VL of the monoclonal antibody produced by the hybridoma cell line deposited under ATCC Accession No. PTA-9693.
Seq id no-defined vh/vl cdr set for toxin a or toxin b binding
An isolated antibody or an antigen-binding fragment thereof that specifically binds toxin A of C. difficile wherein the VH comprises the CDR1, CDR2, and CDR3 of SEQ ID NO:1 or SEQ ID NO:2 and the VL comprises the CDR1, CDR2, and CDR3 of SEQ ID NO:3 or SEQ ID NO:4; or specifically binds toxin A of C. difficile wherein the VH comprises the CDR1, CDR2, and CDR3 of SEQ ID NO:5 or SEQ ID NO:6 and the VL comprises the CDR1, CDR2, and CDR3 of SEQ ID NO:7; or specifically binds toxin B of C. difficile wherein the VH comprises the CDR1, CDR2, and CDR3 of SEQ ID NO:8 or SEQ ID NO:9 and the VL comprises the CDR1, CDR2, and CDR3 of SEQ ID NO:10.
Residue span-defined cdr toxin a or toxin b binder
An isolated antibody or an antigen-binding fragment thereof that specifically binds toxin A of C. difficile wherein the VH comprises a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO:1, a CDR2 comprising amino acid residues 50 to 65 of SEQ ID NO:1, and a CDR3 comprising amino acid residues 95 to 102 of SEQ ID NO:1, and the VL comprises a CDR1 comprising amino acid residues 24 to 34 of SEQ ID NO:3, a CDR2 comprising amino acid residues 50 to 56 of SEQ ID NO:3, and a CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO:3; or specifically binds toxin A of C. difficile wherein the VH comprises a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO:5, a CDR2 comprising amino acid residues 50 to 55 of SEQ ID NO:5, and a CDR3 comprising amino acid residues 95 to 102 of SEQ ID NO:5, and the VL comprises a CDR1 comprising amino acid residues 24 to 33 of SEQ ID NO:7, a CDR2 comprising amino acid residues 49 to 55 of SEQ ID NO:7, and a CDR3 comprising amino acid residues 88 to 94 of SEQ ID NO:7; or specifically binds toxin B of C. difficile wherein the VH comprises a CDR1 comprising amino acid residues 31 to 36 of SEQ ID NO:8, a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO:8, and a CDR3 comprising amino acid residues 99 to 108 of SEQ ID NO:8, and the VL comprises a CDR1 comprising amino acid residues 24 to 34 of SEQ ID NO:10, a CDR2 comprising amino acid residues 50 to 56 of SEQ ID NO:10, and a CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO:10.
Overall, the independent claims cover isolated antibodies and antigen-binding fragments that specifically bind C. difficile toxin A and/or toxin B, with VH/VL CDR compositions defined either by ATCC-deposited hybridoma-derived antibodies or by specific SEQ ID NO CDR sets and residue spans.
Stated Advantages
Neutralization of C. difficile toxins A and/or B, including neutralization potency against hypervirulent strains.
Protection in vivo in mouse and hamster CDAD models, including durable protection and relapse prevention.
Intended for treatment and prophylaxis, including recurrence, of C. difficile infection and C. difficile-associated disease.
Associated with demonstrated binding and neutralization outcomes against clinical isolates and hypervirulent BI/NAP1/027 strains.
Documented Applications
Therapeutic use for a subject with a Clostridioides difficile infection, C. difficile-associated disease, or C. difficile-associated diarrhea (CDAD) by administering a composition including the claimed antibody or antigen-binding fragment.
Treatment and prophylaxis of C. difficile infection.
Treatment and prophylaxis of C. difficile-associated disease (CDAD).
Treatment and prophylaxis of recurrence associated with hypervirulent BI/NAP1/027 strains.
Use in pharmaceutical compositions and kits for administration and delivery.
Vaccine/immunogen constructs using toxin epitope-containing fragments or peptides to produce corresponding immune response outcomes.
In vitro neutralization and binding characterization assays of anti-toxin monoclonal antibodies against toxin A and/or toxin B.
In vivo protection studies in mouse and hamster CDAD models.
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