The other authors declare no conflicts of interest. == Footnotes == Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. == Supplementary information == Supplementary informationaccompanies this paper at 10.1186/s12967-020-02484-9. == Recommendations == == Associated Data == This section collects any data citations, data availability statements, or supplementary materials included in this article. == Supplementary Materials == Additional file 1: Physique S1.Fitted curves for domain specific ELISAs. both in vitro and in the presence of a human immune system in humanized tumor mice. == Results == B100 not only efficiently blocks Medetomidine HCl cell proliferation but more importantly induces apoptotic tumor cell death. Detailed in vitro analyses of B100 in comparison to trastuzumab (and pertuzumab) revealed comparative HER2 internalization and recycling capacity, comparable Fc receptor signaling, but different HER2 epitope acknowledgement with high binding and treatment efficiency. In trastuzumab resistant SK-BR-3 based humanized tumor mice the B100 treatment eliminated the primary tumor but even more importantly eradicated metastasized tumor cells in lung, liver, brain, and bone marrow. == Conclusion == Overall, B100 demonstrated an enhanced anti-tumor activity both in vitro and in an enhanced preclinical HTM in vivo model compared to trastuzumab or pertuzumab. Thus, the use of B100 is usually a promising option to complement and to enhance established treatment regimens for HER2-positive Medetomidine HCl (breast) cancer and to overcome trastuzumab Medetomidine HCl resistance. Extended preclinical analyses using appropriate models and clinical investigations are warranted. Keywords:Anti-HER2 antibody, Breast cancer, Treatment efficiency, Humanized tumor mice, Monoclonal antibody == Background == The receptor tyrosine kinase Human Epidermal Growth Factor Receptor 2 (HER2) is usually a driver of breast carcinogenesis and progression. It plays a pivotal role in the regulation of cell proliferation and its downstream signaling pathways are involved in the regulation of migration, differentiation, and apoptosis [1]. HER2 is usually overexpressed in about 20 % of all breast cancers (BC), mostly caused by HER2 gene amplification, and has been associated with a worse prognosis and a higher risk of relapse [2]. Foxd1 In contrast to its molecular relatives HER1, HER3, and HER4 and due to its unique extracellular 3D conformation, the HER2 receptor does not bind any known native ligand. Receptor activation occurs mainly by homodimerization- and heterointeraction with other receptor family members. Upon activation, the Ras-MAPK pathway triggers tumor cell proliferation and the mTOR signaling promotes cell survival by counteracting pro-apoptotic signals [3]. Trastuzumab (Herceptin), in the beginning generated by Genentech Inc. (San Francisco, CA, USA) as monoclonal antibody 4D5, is usually a recombinant humanized monoclonal IgG1 antibody that binds to the extracellular domain name IV of the HER2 protein close to the cell membrane [4]. Upon binding to HER2 [5] trastuzumab ligand independently affects homo-dimerization, triggers antibody dependent cellular cytotoxicity (ADCC) by activating CD16-positive immune cells, and it prevents shedding of the extracellular receptor domain name [3] which normally would cause a constitutively hyper-activated p95-HER2 domain name [6]. However, 50% of patients with HER2-positive breast cancer dont show response either ab initio or acquire resistance during treatment [7]. Accordingly, there is still a significant high rate of malignancy related death amongst the group of HER2-positive BC patients [8]. Another HER2-specific humanized monoclonal antibody pertuzumab (Perjeta, Genentech Inc.) recognizes a rather distal located extracellular HER2 epitope and became clinically approved in combination with trastuzumab for the treatment of BC patients in the neoadjuvant and adjuvant setting. Pertuzumab complements the trastuzumab mediated therapeutic effects predominantly by preventing HER2 (hetero-)dimerization and receptor phosphorylation [911]. The application of both trastuzumab and pertuzumab in combination (but not the use of pertuzumab alone) enhanced the pathological total response rates (pCR) from 29 to 46% with locally advanced, inflammatory, or early-stage HER2-positive breast cancer as exhibited by the NeoSphere2 trial [12] . Nevertheless, long term monitoring is still needed to assess the capability of the two antibody based treatment regimens to delay or even prevent distant relapse and to determine the overall survival benefit. Apparently, the combined use of clinically active therapeutic anti-HER2 antibodies is usually a very powerful strategy to further improve the course (and end result) of HER2-positive BC disease, whereby an additive or even synergistic treatment effect has been attributed to different but complementing molecular mechanisms brought on by two immunoglobulins [13,14]. So far, most of the monoclonal antibodies approved for clinical application have been generated in mice. However, mouse strains typically utilized for immunization and antibody generation are usually inbred, are housed under specific pathogen-free.