Antibodies against clostridium difficile toxins and methods of using the same
AssigneeSanofi Pasteur Biologics, LLC
InventorsStephen F. Anderson, Natalie Anosova, Nicola Beltraminelli, Pierre Garrone, Harold Kleanthous, Majid Mehtali, Jianxin Zhang
Life of this patent
Estimating the term…
Abstract
Monoclonal antibodies, or antigen-binding fragments thereof, that bind to Clostridium difficile (C. difficile) toxin A or toxin B and methods of using the same to detect or treat C. difficile infections and/or C. difficile-associated disease.
Claims23
1-6. (canceled)
An isolated monoclonal antibody that binds to an epitope in the glucosyl transferase domain of C. difficile toxin B, wherein the epitope comprises the amino acid sequence SGRNK (SEQ ID NO:234), amino acids 56-80 of SEQ ID NO:231, or amino acids 10-520 of SEQ ID NO:231.
An isolated monoclonal antibody that binds to an epitope in the N-terminal translocation domain of C. difficile toxin B, wherein the epitope comprises amino acids 1110-1530 of SEQ ID NO:231.
An isolated monoclonal antibody that binds to an epitope in the receptor binding domain of C. difficile toxin B, wherein the epitope comprises amino acids 1750-2360 of SEQ ID NO:231.
(canceled)
An isolated, monoclonal antibody that binds to Clostridium difficile toxin B, wherein said antibody comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:92, SEQ ID NO:110, SEQ ID NO:128, SEQ ID NO:146, SEQ ID NO:164, or SEQ ID NO:182 or a light chain variable domain comprising the amino acid sequence of SEQ ID NO:94, SEQ ID NO:112, SEQ ID NO:130, SEQ ID NO:148, SEQ ID NO:166, or SEQ ID NO:184.
(canceled)
An isolated monoclonal antibody that binds to the same epitope of Clostridium difficile toxin B recognized by or that competitively inhibits the binding of toxin B to:
- (a) an antibody having a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:92 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:94;
- (b) an antibody having a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:110 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:112;
- (c) an antibody having a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:128 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:130;
- (d) an antibody having a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:146 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:148;
- (e) an antibody having a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:164 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:166;
- or
- (f) an antibody having a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO:182 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO:184.
17-20. (canceled)
22-28. (canceled)
An isolated nucleic acid that encodes the amino acid sequence of one or more of the complementarity determining regions (CDRs) of a heavy chain variable domain and/or light chain variable domain of an isolated monoclonal antibody that binds to Clostridium difficile toxin A,
- (a) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:2 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:4;
- (b) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:20 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:22;
- (c) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:38 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:40;
- (d) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:56 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:58, or
- (e) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:74 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:76, or
- an isolated monoclonal antibody that binds to Clostridium difficile toxin B,
- (a) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:92 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:94;
- (b) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:110 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:112;
- (c) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:128 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:130;
- (d) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:146 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:148;
- (e) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:164 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:166;
- or
- (f) wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO:182 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO:184.
An isolated nucleic acid that encodes the amino acid sequence of the heavy and/or light chain variable regions of an isolated monoclonal antibody that binds to Clostridium difficile toxin A,
- (a) wherein the heavy chain variable domain comprises a complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:6;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:8;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:10;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:13;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:15;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:17;
- (b) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:24;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:26;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:28;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:31;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:33;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:35;
- (c) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:42;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:44;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:46;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:49;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:51;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:53;
- (d) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:60;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:62;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:64;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:67;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:69;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:71;
- or
- (e) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:78;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:80;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:82;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:85;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:87;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:89 or
- an isolated monoclonal antibody that binds to Clostridium difficile toxin B,
- (a) wherein the heavy chain variable domain comprises a complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:96;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:98;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:100;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:103;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:105;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:107;
- (b) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:114;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:116;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:118;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:121;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:123;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:125;
- (c) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:132;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:134;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:136;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:139;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:141;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:143;
- (d) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:150;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:152;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:154;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:157;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:159;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:161;
- (e) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:168;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:170;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:172;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:175;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:177;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:179;
- or
- (f) wherein the heavy chain variable domain comprises a CDR1 comprising the amino acid sequence of SEQ ID NO:186;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:188;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:190;
- and wherein the light chain variable domain comprises:
- a CDR1 comprising the amino acid sequence of SEQ ID NO:193;
- a CDR2 comprising the amino acid sequence of SEQ ID NO:195;
- and a CDR3 comprising the amino acid sequence of SEQ ID NO:197.
Dependencies are inferred from the claim text.