In vitro and in vivo antitumor effect of a trivalent bispecific antibody targeting ErbB2 and CD16.
In order to optimize the structure of bispecific antibody (BsAb) and minimize its toxicity, we developed a trivalent anti-ErbB2/anti-CD16 BsAb. This BsAb possesses three antigen binding sites, two antigen binding sites in the form of scFvs targeting the tumor cells overexpressing ErbB2 and a monovalent Fab fragment redirecting NK cells. Critical for this BsAb is its capacity to trigger cytotoxicity of the effector cells in vitro and in vivo. In the present study, we demonstrated that the BsAb is capable of binding to ErbB2 extracellular domain on SKBR3 cells and effectively direct the cytotoxic activities of effector cells to SKBR3 cells even at a low concentration. The BsAb was more effective to SKBR3 cells than to MCF-7 cells, indicating that the killing of tumor cells was dependent on the density of ErbB2 molecules on cell surface. Furthermore, the BsAb was more potent than anti-ErbB2 single chain antibody (scFv)-Fc fusion proteins in the cytotoxicity assay and in SKOV3 xenograft animals. Improved efficacy demonstrates that the BsAb may be valuable to be further modified and optimized for the treatment of malignant cells in a minimal residual disease.
Lu
Han
H
Institute of Basic Medical Sciences, Beijing, PR China.
Shi
Ming
M
Wang
Mingli
M
Xie
Zhigang
Z
Hu
Meiru
M
Yu
Ming
M
Shen
Beifen
B
Ma
Yuanfang
Y
Guo
Ning
N
D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry*; D001665:Binding Sites; D019556:COS Cells; D045744:Cell Line, Tumor; D002469:Cell Separation; D002522:Chlorocebus aethiops; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007167:Immunotherapy / Q000379:methods; D066298:In Vitro Techniques; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017452:Receptors, IgG / Q000096:biosynthesis*; D013997:Time Factors
D018033:Antibodies, Bispecific; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D017452:Receptors, IgG; C508053:ERBB2 protein, human