Abstract
Human epidermal growth factor receptor 2 (HER2) overexpression occurs in various types of cancers. Regarding the anti-HER2 targeted therapies showed superior treatment outcomes in several (pre)clinical studies, we used multimodality image to rapidly select novel HER2-targeting antibodies for further therapeutics development. The four anti-HER2 antibodies (H32 IgG, 75 IgG, 61 IgG, and trastuzumab) labeled with either In-111 or a DyLight680 fluorescent dye were applied to perform cellular uptake, endocytosis, optical/microSPECT/CT imaging and biodistribution studies. In vitro and in vivo relative effectiveness of these antibodies were also compared in an N87 gastric cancer xenograft model. The internalized radioactivity of [111In]61 IgG in N87 cells increased from 33% at 12 hr to 56% at 48 hr after incubation, while the majority of other antibodies stayed on the cell membranes. Among these antibodies, 61 IgG showed the highest accumulation in tumors with the tumor-to-muscle ratio (T/M) of 131 ± 61.4 and 19.13 ± 3.42 conducted by IVIS and microSPECT/CT, respectively. We demonstrated that multimodality imaging is a reliable approach for selecting potential antibodies and found that 61 IgG manifested significant tumor accumulation with elevated internalization rate thus could be a suitable candidate for further development of new HER2-targeted therapies.
Highlights
Gastric cancer is the fourth most common cancer and the fourth leading cause of cancer death around the world, accounting for an estimated 28,000 new cases and 10,960 deaths in 20171
The antigen binding affinity of anti-Human epidermal growth factor receptor 2 (HER2) antibodies and their derivatives to HER2 ECD was analyzed by enzyme-linked immunosorbent assay (ELISA) (Fig. 1a), demonstrating that the target affinities of our antibodies, including H32 IgG, 61 IgG, and 75IgG were all higher than that of trastuzumab
We found the radioactivity of [111In]labeled trastuzumab, H32 IgG, and 61 IgG significantly retained in BT474 human breast cancer xenografts as well as in N87 tumors (Figure S1b)
Summary
Gastric cancer is the fourth most common cancer and the fourth leading cause of cancer death around the world, accounting for an estimated 28,000 new cases and 10,960 deaths in 20171. Trastuzumab, the first Food and Drug Administration (FDA)-approved HER2-targeting recombinant humanized monoclonal antibody for the treatment of breast cancer, has been labeled with different radioisotopes for diagnosis and radiation therapy[6,7,8]. An antibody-drug conjugate (ADC), named trastuzumab-emtansine (T-DM1), reached the market in 2013 for the treatment of HER2-positive metastatic breast cancer and showed an impressive clinical efficacy[9,10]. Marquez et al showed that increased tumor uptake of 89Zr-pertuzumab in the presence of unlabeled trastuzumab[14], implying its better affinity toward HER2 and the potential of using pertuzumab-derived ADC to treat patients
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