Abstract
Overexpression of HER2 has been reported in many types of cancer, making it a perfect candidate for targeted immunotherapy. The combination of two FDA approved monoclonal antibodies (mAbs), trastuzumab and pertuzumab, has more robust anti-tumor activity in patients with HER2-overexpressing breast cancer. We recently produced a new humanized anti-HER2 mAb, hersintuzumab, which recognizes a different epitope than trastuzumab and pertuzumab on HER2. This mAb, in combination with trastuzumab, exhibits more potent anti-tumor activity than each parental mAb alone. Here we have developed a novel bispecific anti-HER2 antibody (BsAb) designated as trasintuzumab, composed of trastuzumab and hersintuzumab, using dual variable domain immunoglobulin (DVD-Ig) technology. Both variable domains of trasintuzumab are fully functional and have similar affinities to the parental mAbs and are also able to bind to natural HER2 on the surface of several HER2-expressing cell lines. Trasintuzumab was found to inhibit the growth of different types of tumor cell lines through suppression of the AKT and ERK signaling pathways as efficiently as the combination of the parental mAbs. It also induced tumor regression as potently as the combination of the two mAbs in nude mice bearing ovarian and gastric cancer xenografts. Our data suggest that trasintuzumab may be a promising BsAb therapeutic candidate for the treatment of HER2-overexpressing cancers.
Highlights
The human HER family includes HER1 (ErbB1, known as EGFR), HER2 (ErbB2, c-erbB2, or HER2/neu), HER3 (ErbB3), and HER4 (ErbB4) molecules
The structure of dual variable domain immunoglobulin (DVD-Ig) were analyzed by SDS-PAGE, and the results showed similar patterns for both DVD-Igs with a monomeric form (200 kDa) under nonreducing and two monomeric heavy (~65 kDa) and light (~40 kDa) chains under reducing conditions (Figure 1B)
Dual specific binding and affinity of DVD-Igs to subdomain I+II, subdomain III+IV, and full extracellular domains (ECD) of human HER2 were assessed by a HER2-specific ELISA
Summary
The human HER (human epidermal growth factor receptor) family includes HER1 (ErbB1, known as EGFR), HER2 (ErbB2, c-erbB2, or HER2/neu), HER3 (ErbB3), and HER4 (ErbB4) molecules. These receptors are structurally similar and their hetero/homo dimerizations play important roles in cell differentiation, growth, and survival [1]. Among this family, HER2 is studied more extensively. It is a 185 kDa protein with four extracellular domains (ECD) and an intracellular tyrosine kinase domain, which mainly signals through phosphatidylinositol-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways [2]. Overexpression of HER2 is associated with disease prognosis and has been observed in approximately 25%–30% of breast cancers, 6%–35% of gastric cancers, 9%–32% of ovarian cancers, and 25%–78% of prostate cancers [3]
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