Abstract
BackgroundAntibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients. Trastuzumab that targets the human epidermal growth factor related receptor 2 (HER2) is one of the greatest success stories in this field. For decades, trastuzumab based treatment regimens are significantly improving the prognosis of HER2-positive breast cancer patients both in the metastatic and the (neo-) adjuvant setting. Nevertheless, ≥ 50% of trastuzumab treated patients experience de-novo or acquired resistance. Therefore, an enhanced anti-HER2 targeting with improved treatment efficiency is still aspired.MethodsHere, we determined cellular and molecular mechanisms involved in the treatment of HER2-positive BC cells with a new rabbit derived HER2 specific chimeric monoclonal antibody called “B100″. We evaluated the B100 treatment efficiency of HER2-positive BC cells with different sensitivity to trastuzumab both in vitro and in the presence of a human immune system in humanized tumor mice.ResultsB100 not only efficiently blocks cell proliferation but more importantly induces apoptotic tumor cell death. Detailed in vitro analyses of B100 in comparison to trastuzumab (and pertuzumab) revealed equivalent HER2 internalization and recycling capacity, similar Fc receptor signaling, but different HER2 epitope recognition 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.ConclusionOverall, 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 a promising option to complement and to enhance established treatment regimens for HER2-positive (breast) cancer and to overcome trastuzumab resistance. Extended preclinical analyses using appropriate models and clinical investigations are warranted.
Highlights
Antibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients
When trastuzumab and pertuzumab were applied in combination a strong reduction of the S-phase fractions (SPF) was observed in SK-BR-3 compared to untreated (p < 0.001) and to trastuzumab only treated cells (p < 0.05) as well as in MDA-MB-453 treated compared to untreated (p < 0.01) cells
In addition to the binding competition assay of AK57, B100, and B106 vs. trastuzumab and pertuzumab we identified the extracellular subdomain III of human epidermal growth factor related receptor 2 (HER2) as the binding epitope of B100 by another ELISA coated with subdomain specific peptides
Summary
Antibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients. There is still a significant high rate of cancer related death amongst the group of HER2-positive BC patients [8] Another HER2-specific humanized monoclonal antibody pertuzumab (PerjetaTM, 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 [9,10,11] The application of both trastuzumab and pertuzumab in combination (but not the use of pertuzumab alone) enhanced the pathological complete response rates (pCR) from 29 to 46% with locally advanced, inflammatory, or early-stage HER2positive breast cancer as demonstrated by the NeoSphere trial [12]. The combined use of clinically active therapeutic anti-HER2 antibodies is a very powerful strategy to further improve the course (and outcome) of HER2positive BC disease, whereby an additive or even synergistic treatment effect has been attributed to different but complementing molecular mechanisms triggered by two immunoglobulins [13, 14]
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