Development of humanized monoclonal antibody TMA-15 which neutralizes Shiga toxin 2.
A murine monoclonal antibody (MAb), VTm1.1, specifically recognizing and neutralizing Shiga toxin 2 (Stx2), was obtained. To prevent a humoral response against murine antibody when used clinically, a humanized antibody was constructed by combining the complementarity-determining regions of VTm1.1 with human framework and constant regions. In addition, several amino acids in the framework were changed to improve the binding affinity of the antibody and further reduce its potential immunogenicity. The humanized antibody, TMA-15, recognized the B-subunit of Stx2 and had affinity for Stx2 of 3.3 x 10(-9) M, within two-fold of that of the original murine antibody. TMA-15 neutralized the cytotoxicity of Stx2 and several different Stx2 variants in vitro, and it completely protected mice from death in a Stx2-challenged mice model. These results suggest that TMA-15 will have clinical potency in Stx-producing Escherichia coli infections, including E. coli O157 infections.
Kimura
Tsuyoshi
T
Teijin Institute for Biomedical Research, Teijin Limited, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan. t.kimura@teijin.co.jp
Co
Man Sung
MS
Vasquez
Maximiliano
M
Wei
Sharon
S
Xu
Hattie
H
Tani
Shinobu
S
Sakai
Yuri
Y
Kawamura
Takashi
T
Matsumoto
Yoh-Ichi
Y
Nakao
Hiroshi
H
Takeda
Tae
T
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009101:Multiple Myeloma; D016415:Sequence Alignment; D022641:Shiga Toxin 2 / Q000276:immunology*; D013154:Spleen
D000911:Antibodies, Monoclonal; D022641:Shiga Toxin 2