Clostridium difficile antibodies
Compositions and methods for the treatment or prevention of Clostridium difficile infection in a subject are provided. The compositions comprise antibodies to Clostridium difficile toxin A. The methods provide for administering the antibodies to a subject in an amount effective to reduce or eliminate or prevent relapse from Clostridium difficile bacterial infection.
1. An isolated monoclonal antibody, or an antigen-binding portion thereof comprising a heavy chain variable region and a light chain variable region,
wherein the heavy chain variable region comprises three complementarity determining regions (CDRs), CDR1, CDR2, and CDR3, having the amino acid sequences set forth in SEQ ID NOs: 45, 46, and 47, respectively and wherein the light chain variable region comprises three CDRs, CDR1, CDR2, and CDR3, having the amino acid sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively, and
wherein the antibody or antigen-binding portion thereof specifically binds to Clostridium difficile ( C. difficile ) toxin A.
2. The antibody or antigen-binding portion thereof of claim 1 ,
wherein the heavy chain variable region comprises the amino acid sequence SEQ ID NO: 44 and wherein the light chain variable region comprises the amino acid sequence SEQ ID NO:36.
3. The antibody or antigen-binding portion thereof of claim 1 , wherein the dissociation constant (K D ) of the antibody, or antigen-binding portion thereof, is less than about 1×10 −11 M.
4. The antibody or antigen-binding portion thereof of claim 1 , wherein the antibody, or antigen-binding portion thereof, is humanized or chimeric.
5. The antibody or antigen-binding portion thereof of claim 1 , wherein the antibody, or antigen-binding portion thereof, is selected from the group consisting of: (a) an scFv; (b) a Fab fragment; (c) an F(ab′)2; and (d) a disulfide linked Fv.
6. The antibody or antigen-binding portion thereof of claim 1 , wherein the antibody, or antigen-binding portion thereof, comprises at least one constant domain selected from the group consisting of: a) an IgG constant domain; and (b) an IgA constant domain.
7. The antibody or antigen-binding portion thereof of claim 1 , wherein the antibody, or antigen-binding portion thereof, binds to fragment 4 of C. difficile toxin A.
8. The antibody or antigen-binding portion thereof of claim 1 , wherein, in an in vivo toxin A challenge experiment, when the antibody, or an antigen-binding portion thereof, is administered to a mammal at a dosage ranging from about 8 mg/kg body weight to about 13 mg/kg body weight about 24 hours before the mammal is exposed to greater than about 100 ng of C. difficile toxin A, the chance of survival for the mammal is greater than about 80% within about 7 days.
9. The antibody or antigen-binding portion thereof of claim 1 , wherein the antibody, or antigen-binding portion thereof, at a concentration ranging from about 4 μM to about 17 μM, neutralizes greater than about 40% of about 150 ng/ml C. difficile toxin A in an in vitro neutralization assay.
10. The antibody or antigen-binding portion thereof of claim 1 , and at least one pharmaceutically acceptable carrier.
11. A method of treating C. difficile -associated disease comprising administering to a subject an effective amount of the antibody, or antigen-binding portion thereof, of claim 1 .
12. The method of claim 11 , wherein the antibody, or antigen-binding portion thereof, is administered intravenously, subcutaneously, intramuscularly or transdermally.
13. The method of claim 11 , further comprising the step of administering to the subject a second agent.
14. The method of claim 13 , wherein the second agent is a different antibody or fragment thereof.
15. The method of claim 13 , wherein the second agent is an antibiotic.
16. The method of claim 15 , wherein the antibiotic is vancomycin, metronidazole, or fidaxomicin.