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The Trifunctional Antibody Ertumaxomab Destroys Tumor Cells That Express Low Levels of Human Epidermal Growth Factor Receptor 2

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The Trifunctional Antibody Ertumaxomab Destroys Tumor Cells That Express Low Levels of Human Epidermal Growth Factor Receptor 2 Published OnlineFirst May 12, 2009; DOI: 10.1158/0008-5472.CAN-08-2861 Research Article The Trifunctional Antibody Ertumaxomab Destroys Tumor Cells That Express Low Levels of Human Epidermal Growth Factor Receptor 2 Michael Ja¨ger,1 Alexandra Schoberth,1 Peter Ruf,1 Ju¨rgen Hess,2 and Horst Lindhofer1,2 1TRION Research GmbH, Martinsried, Germany and 2TRION Pharma GmbH, Munich, Germany Abstract The humanized monoclonal anti-HER2/neu antibody trastuzu- Human epidermal growth factor receptor 2 (HER2/neu) is an mab inhibits growth of tumor cell lines that strongly express the important target for the treatment of the breast cancers in HER2/neu antigen (6). Several clinical studies have shown the which it is overexpressed. However, no approved anti-HER2/ greatest benefit from trastuzumab treatment (7, 8) among women neu therapyis available for the majorityof breast cancer with metastatic breast cancers (scored 3+ or 2+ by immunohis- patients, who express HER2/neu at low levels (with scores of tochemisty), and with HER2 gene amplifications (confirmed by 1+ or 2+/fluorescence in situ hybridization–negative). The fluorescent in situ hybridization; FISH). Based on these results, trifunctional antibodyertumaxomab targets HER2/neu, CD3, assessment of the HER2/neu status is absolutely required for all and activating Fc; receptors. In presence of ertumaxomab, breast cancer patients who may be considered for trastuzumab tri-cell complexes consisting of tumor cells, T cells, and therapy. However, trastuzumab therapy cannot be offered to the majority of breast cancer patients who have low levels of HER2/neu accessorycells form to cause tumor cell lysis.In a phase I trial with metastatic breast cancer patients, ertumaxomab could be expression (scored 1+ and 2+) and negative FISH results. Ertumaxomab is a new member of a family of trifunctional applied safelyand resulted in radiographicallyconfirmed  clinical responses. In this study, we compare ertumaxomab- bispecific antibodies (anti-HER2/neu anti-CD3). Kiewe and and trastuzumab-mediated killing of cancer cell lines that colleagues (9) presented the first promising clinical data on the express HER2/neu at low and high levels. Under optimal safety and efficacy of ertumaxomab in the treatment of metastatic conditions for trastuzumab-mediated destruction of HER2/ breast cancer patients with different HER2/neu expression levels. neu-overexpressing cells, onlyertumaxomab was able to Such as BiUII and catumaxomab, which target EpCAM instead of mediate the elimination of tumor cell lines that express HER2/neu, ertumaxomab evokes a concerted interaction of HER2/neu at low levels (1+). Ertumaxomab-mediated activity different immune cell types directed against the tumor (10, 11). was accompanied bya Th1-based cytokinerelease, a unique Such as BiUII, ertumaxomab might simultaneously recruit and g g mode of action of trifunctional antibodies. Competitive activate Fc RI and Fc RIII-positive accessory cells (i.e., monocytes, binding studies with trastuzumab and 520C9 mapped the macrophages, natural killer cells, and dendritic cells) through its unique isotype combination (mouse IgG2a and rat IgG2b), leading binding site of ertumaxomab to the extracellular regions II and III of the HER2/neu ectodomain. This site is distinct from to the phagocytosis of the tumor cells (12). The importance of the the binding site of trastuzumab, so that HER2/neu-expressing mouse/rat hybrid Fc region in the process of immunization has tumor cells can be eliminated byertumaxomab in the been shown in immunocompetent mouse tumor models, using the presence of high amounts of trastuzumab. The abilityof trifunctional surrogate antibody BiLu (anti-human EpCAM x anti- ertumaxomab to induce cytotoxicity against various tumor murine CD3; refs. 13, 14). As evidenced by Riesenberg and cell lines, including those with low HER2/neu antigen density, colleagues (15), perforin-mediated cytotoxicity may contribute to mayprovide a novel therapeutic option for breast cancer the antitumor response. Taken together, these data suggest that patients who are not eligible for trastuzumab treatment. ertumaxomab may induce the formation of a tri-cell-complex consisting of HER2/neu+ + g + [Cancer Res 2009;69(10):4270–6] tumor cells, CD3 T cells, and Fc R accessory cells, leading to efficient elimination of tumor cells. In this study, we report on the high efficacy of the trifunctional antibody ertumaxomab to specifically eradicate different HER2/ Introduction neu-positive tumor cell lines, accompanied by the activation of a The proto-oncogene HER2 codes for the human epidermal Th1-type cytokine pattern. In contrast to the monospecific growth factor receptor 2 (HER2/neu), which is overexpressed in humanized antibody trastuzumab, ertumaxomab destroys tumor 20% to 30% of breast cancer patients (1–3). HER2/neu over- cell lines with high and also with low HER2/neu expression. In expression is usually based on gene amplification. It is correlated addition, we are able to show that trastuzumab and ertumaxomab with a poor prognosis, reducing progression-free outcomes and recognize different epitopes on Her2/neu. The possible clinical overall survival (4, 5). HER2/neu is an important target for implications of these findings are discussed. antibody-mediated therapy in breast cancer patients. Materials and Methods Antibodies, effector cells, and target cell lines. We used freshly Requests for reprints: Horst Lindhofer, TRION Pharma GmbH, Frankfurter Ring harvested peripheral blood mononuclear cells (PBMC) from healthy donors 193a, 80807 Munich, Germany. Phone: 49-89-324266100; Fax: 49-89-324266199; E-mail: as effector cells. The cells were purified by density centrifugation through [email protected].  j I2009 American Association for Cancer Research. Ficoll Histopaque (PAN Biotech) at 897 g, 15 min, 20 C. They were doi:10.1158/0008-5472.CAN-08-2861 washed twice with PBS without Mg2+ or Ca2+ (PAN Biotech), and Cancer Res 2009; 69: (10). May 15, 2009 4270 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst May 12, 2009; DOI: 10.1158/0008-5472.CAN-08-2861 Ertumaxomab Lyses Tumor Cells with Low HER2/neu Levels Figure 1. HER2/neu-expressing profiles of used cell lines: A, SK-BR-3, (B) HCT-8, (C) BT-20, and (D) SK-LU-1. FACS, fluorescence activated cell sorter histogram, FL1-H = 2502A + secondary detection antibody rat anti-mouse IgG H+L FITC, mouse IgG2a isotype control Me361 (TRION Research) + secondary detection antibody rat anti-mouse IgG H+L FITC; MFI, mean fluorescence intensity; SABC, specific antigen binding capacity as determined by DAKO QIFIKIT. centrifuged at 458  g, for 10 min, at 20jC. The supernatant was removed, SPEC HER2/CEN 17 Dual Color Probe is a mixture of an orange and the pellet was resuspended in 20 mL RPMI 1640, supplemented with fluorochrome direct–labeled CEN 17 probe, specific for the a satellite 2 mmol/L glutamine, 1 mmol/L sodium pyruvate, 1 mmol/L nonessential centromeric region of chromosome 17 (D17Z1), and a green fluorochrome amino acids, and 10% FCS (PAN Biotech). Cell number and viability direct–labeled SPEC HER2 probe, specific for the HER2 gene at 17q12. After were determined using a Neubauer counting chamber after trypan blue counterstaining with 4¶,6-diamidino-2-phenylindole (Zytovision), slides were staining (Sigma-Aldrich). The breast cancer cell lines SK-BR-3 (ATCC evaluated at Â100 oil magnification, applying a computerized image HTB-30) and BT-20 (ATCC HTB-19), the human ileocaecal adenocarcinoma analysis (MDS; Applied Imaging). cell line HCT-8 (ATCC CCL-244), and the lung cancer cell line SK-LU-1 Fluorescence-activated cell sorter binding competition analysis. (ATCC HTB-57) served as target cells in cytotoxicity assays with PBMC Highly positive HER2/neu SK-BR-3 cells were preincubated with varying effector cells, followed by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]- concentrations of either 520C9 (10,000–100 ng/mL) or trastuzumab (10,000– 2H-tetrazolium-5-carboxanilide inner salt (XTT) cell proliferation assess- 100 ng/mL) for 10 min, followed by addition of a constant concentration of ment (16). The trifunctional antibody ertumaxomab with anti-HER2/neu  ertumaxomab (1,000 ng/mL), and further incubation for 45 min. After a anti-CD3 antigen specificities was manufactured by TRION Pharma. The washing step, ertumaxomab cell binding was detected by fluorescence- HER2/neu-specific monoclonal mouse antibodies 2502A and 520C9 (ATCC activated cell sorting (FACS) with an anti-rat IgG (H+L) FITC-labeled HB-8696; ref. 17) were produced by TRION Research. 2502A constitutes the secondary detection antibody (Dianova). HER2/neu binding arm of ertumaxomab. The humanized IgG1 antibody Cytotoxicity assay. Effector cells (2  105; PBMC) and target cells trastuzumab (Roche) also recognizes the HER2/neu protein. (SK-BR-3, HCT-8, BT-20, or SK-LU-1) at varying E/T ratios were coincubated Quantitative determination of the cell surface antigen HER2/neu. in flat-bottomed 96-well plates (Greiner) with either trastuzumab or HER2/neu antigen expression on the surface of tumor target cell lines was ertumaxomab and combinations of different antibodies concentrations as quantified using DAKO QIFIKIT (DAKO Cytomation), according to the indicated. PBMCs coincubated with tumor cells alone (allogeneic setting) manufacturer’s protocol. HER2/neu-specific 2502A was used as the primary were used as controls. After 4 d, PBMCs were discarded
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