Fully human HER2/cluster of differentiation 3 bispecific antibody triggers potent and specific cytotoxicity of T lymphocytes against breast cancer

Abstract

The use of a bispecific antibody (BsAb) is a promising and highly specific approach to cancer therapy. In the present study, a fully human recombinant single chain variable fragment BsAb against human epidermal growth factor receptor (HER)2 and cluster of differentiation (CD)3 was constructed with the aim of developing an effective treatment for breast cancer. HER2/CD3 BsAb was expressed in Chinese hamster ovary cells and purified via nickel column chromatography. Flow cytometry revealed that the HER2/CD3 BsAb was able to specifically bind to HER2 and CD3-positive cells. HER2/CD3 BsAb was able to stimulate T-cell activation and induce the lysis of cultured SKBR-3 and BT474 cells in the presence of unstimulated T lymphocytes. HER2/CD3 BsAb efficiently inhibited the growth of breast cancer tissue by activating and inducing the proliferation of tumor tissue infiltrating lymphocytes. Therefore, HER2/CD3 BsAb is a potent tool which may be a suitable candidate for the treatment of breast cancer.

Monoclonal antibody-based therapeutics, targeting the epidermal growth factor receptor family: from herceptin to Pan HER

“…It also could be effective in trastuzumab‐resistant patients and those tumour cells with low level HER2 expression . T‐cell activation is not dependent on HER2 expression levels, hence it can be also useful in HER2 low expressing tumour cells, resistant tumour cells or cancer stem cells …”

“…[79,90] T-cell activation is not dependent on HER2 expression levels, hence it can be also useful in HER2 low expressing tumour cells, resistant tumour cells or cancer stem cells. [4,91]…”

“…Thus, they could be considered as proto-oncogenes and can cooperate in tumour cell proliferation and progression. [4][5][6] HER1 and HER2 are mostly low while HER3 and HER4 are moderate to high expressed in all normal cells. Overexpression of the EGFR family members except for HER4 in cancers leads to poor prognosis and outcome.…”

“…The EGFR including HER1 (EGFR), HER2, HER3 and HER4 are transmembrane proteins involved in various downstream cellular signalling such as PI3K/AKT and RAS/RAF pathways (Figure ). Thus, they could be considered as proto‐oncogenes and can cooperate in tumour cell proliferation and progression . HER1 and HER2 are mostly low while HER3 and HER4 are moderate to high expressed in all normal cells.…”

Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection

“…As later generation formats (i.e. BiTE [34], Dual-Affinity Re-Targeting (DART) antibodies [17], Tandem Diabodies (TandAb) [21*], and others [4*, 5]) advanced into pre-clinical and clinical development, they appeared to potently eliminate targets expressing their TAA in the absence of either costimulatory molecules or the presence of IL-2 pre-activated T cells [16, 17, 21*, 25, 35–38*, 39]. As described above, a T cell population independent of costimulatory signaling, those having the CD8 + and CD4 + memory phenotype, is the major contributor to the cytotoxic potency of BiTEs, and this is probably also the case for the other later generation formats (Figure 1).…”