Abstract
Lewis Y antigen, a glycan highly expressed on most epithelial cancers, was targeted for cancer treatment but lacked satisfactory results in some intractable and refractory cancers. Thus, it is highly desirable to develop an effective therapy against these cancers, hopefully based on this target. In this work, we constructed a novel T cell-engaging bispecific antibody targeting Lewis Y and CD3 (m3s193 BsAb) with the IgG-[L]-scfv format. In vitro activity of m3s193 BsAb was evaluated by affinity assay to target cells, cytotoxicity assay, cytokines releasing assay, and T cells proliferation and recruiting assays. Anti-tumor activity against gastric cancer was evaluated in vivo by subcutaneous huPBMCs/tumor cells co-grafting model and huPBMCs intravenous injecting model. In vitro, m3s193 BsAb appeared to have a high binding affinity to Lewis Y positive cells and Jurkat cells. The BsAb showed stronger activity than its parent mAb in T cell recruiting, activation, proliferation, cytokine release, and cytotoxicity. In vivo, m3s193 BsAb not only demonstrated higher therapeutic efficacy in the huPBMCs/tumor co-grafting gastric carcinoma model than the parent mAb but also eliminated tumors in the model of intravenous injection with huPBMCs. Strong anti-tumor activity of m3s193 BsAb revealed that Lewis Y could be targeted in T cell-engaging BsAb for gastric cancer therapy.
Highlights
Bispecific antibody (BsAb) has achieved a great accomplishment in fighting against diseases, including cancers
Researchers found that knockdown of FUT1, a key enzyme for Lewis Y synthesis, could down-regulate HER2 signaling via EGFR down-regulation to inhibit the proliferation of the gastric cancer cell line (NCI-N87) [29]
The variable heavy chain (VH) sequences and variable light chain (VL) sequences of anti-Lewis Y antibody and Lewis Y-BsAb were derived from murine monoclonal antibody
Summary
Bispecific antibody (BsAb) has achieved a great accomplishment in fighting against diseases, including cancers. Many cancer cell surface antigens, such as CD19, Her, and GD2, were targeted through T cell-engaging BsAbs, showing potent anti-tumor activity [5,6,7]. Researchers found that knockdown of FUT1 (gene of α1,2-fucosyltransferase), a key enzyme for Lewis Y synthesis, could down-regulate HER2 signaling via EGFR down-regulation to inhibit the proliferation of the gastric cancer cell line (NCI-N87) [29]. All these studies suggested that Lewis Y was a promising target for the therapy of epithelial cancers including ovarian, breast, and gastric cancers. We report that this BsAb had an excellent curative effect against Lewis Y positive gastric cancer, showing the potential to be a new therapeutic regent in clinical applications
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