DOCSLIB.ORG

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

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
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 Published Online First on May 12, 2009 as 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 + + g + [Cancer Res 2009;69(10):4270–6] consisting of HER2/neu 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 24, 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 by washing, and antibody for HER2/neu detection and quantification. HER2/neu antigen proliferation of tumor cells was analyzed using the XTT Cell Proliferation quantity is indicated as specific antibody-binding capacity units after kit II, as described by the manufacturer (Roche). Absorbance was measured subtraction of isotype control (mouse IgG2a) background. in a Versamax microplate reader (Molecular Devices), and raw data were FISH analysis. Target cell lines (e.g., SK-BR-3 or HCT-8) were spun down analyzed in Excel XP (Microsoft).
Load more

Recommended publications
  • Press Release Corporate Communications
    Matthias Link Press Release Corporate Communications Fresenius SE & Co. KGaA Else-Kröner-Strasse 1 61352 Bad Homburg Germany T +49 6172 608-2872 F +49 6172 608-2294 [email protected] www.fresenius.com June 22, 2011 Fresenius Biotech obtains reimbursement approval for Removab® antibody in Italy The Italian Medicines Agency, AIFA, has added Fresenius Biotech’s antibody Removab® to its list of reimbursable medications. As of June 25, 2011, use of Removab® for the treatment of malignant ascites in patients with EpCAM-positive carcinomas will be fully reimbursed. Removab® is a trifunctional monoclonal antibody approved throughout the European Union. It has been launched in Austria, France, Germany, Scandinavia and the UK. “The positive decision concerning reimbursement is another step in the successful implementation of our European marketing strategy for Removab®,” said Dr. Christian Schetter, CEO of Fresenius Biotech. “It enables patients in Italy to benefit from treatment with Removab® quickly and without bureaucratic hurdles.” Follow-up results for the pivotal study, recently presented at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO), showed a statistically significant benefit in overall survival for Removab®-treated patients. After six months, nearly 30% of all patients treated with Removab® were still alive, which is a fourfold increase compared to the control group (around 7%). In addition, Removab®-treated patients were shown to have an improved quality of life. ### Page 1/3 About Removab® (catumaxomab) Removab®, with its trifunctional mode of action, represents the first antibody of a new generation. The therapeutic objective of Removab® is to generate a stronger immune response to cancer cells that are the main cause of ascites.
    [Show full text]
  • Targeted and Novel Therapy in Advanced Gastric Cancer Julie H
    Selim et al. Exp Hematol Oncol (2019) 8:25 https://doi.org/10.1186/s40164-019-0149-6 Experimental Hematology & Oncology REVIEW Open Access Targeted and novel therapy in advanced gastric cancer Julie H. Selim1 , Shagufta Shaheen2 , Wei‑Chun Sheu3 and Chung‑Tsen Hsueh4* Abstract The systemic treatment options for advanced gastric cancer (GC) have evolved rapidly in recent years. We have reviewed the recent data of clinical trial incorporating targeted agents, including inhibitors of angiogenesis, human epidermal growth factor receptor 2 (HER2), mesenchymal–epithelial transition, epidermal growth factor receptor, mammalian target of rapamycin, claudin‑18.2, programmed death‑1 and DNA. Addition of trastuzumab to platinum‑ based chemotherapy has become standard of care as front‑line therapy in advanced GC overexpressing HER2. In the second‑line setting, ramucirumab with paclitaxel signifcantly improves overall survival compared to paclitaxel alone. For patients with refractory disease, apatinib, nivolumab, ramucirumab and TAS‑102 have demonstrated single‑agent activity with improved overall survival compared to placebo alone. Pembrolizumab has demonstrated more than 50% response rate in microsatellite instability‑high tumors, 15% response rate in tumors expressing programmed death ligand 1, and non‑inferior outcome in frst‑line treatment compared to chemotherapy. This review summarizes the current state and progress of research on targeted therapy for advanced GC. Keywords: Gastric cancer, Targeted therapy, Human epidermal growth factor receptor 2, Programmed death‑1, Vascular endothelial growth factor receptor 2 Background GC mortality which is consistent with overall decrease in Gastric cancer (GC), including adenocarcinoma of the GC-related deaths [4]. gastroesophageal junction (GEJ) and stomach, is the ffth Tere have been several eforts to perform large-scale most common cancer and the third leading cause of can- molecular profling and classifcation of GC.
    [Show full text]
  • Enhancing Monocyte Effector Functions in Antibody Therapy Against Cancer
    Enhancing monocyte effector functions in antibody therapy against cancer Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kavin Fatehchand, B.S. Biomedical Sciences Graduate Program The Ohio State University 2018 Dissertation Committee: Susheela Tridandapani, Ph.D., Advisor John C. Byrd, M.D. Larry Schlesinger, M.D. Tatiana Oberyszyn, Ph.D. Copyrighted by Kavin Fatehchand 2018 Abstract The immune system plays an important role in the clearance of pathogens and tumor cells. However, tumor cells can develop the ability to evade immune destruction, making the interaction between the immune system and the tumor an important area of research. The overall goal in my graduate studies, therefore, was to find different ways to enhance the innate immune response against cancer cells. First, I focused on monoclonal antibody therapy with reference to the role of monocytes/macrophages as immune effectors. Tumor-specific antibodies bind to cancer cells and create immune-complexes that are recognized by IgG receptors (FcγR) on these immune effector cells. FcγRIIb is the sole inhibitory FcγR that negatively regulates monocyte/macrophage effector responses. In the first part of this study, I examined the ability of the TLR4 agonist, LPS, to enhance macrophage FcγR function. I found that TLR4 activation led to the down-regulation of FcγRIIb through the activation of the March3 ubiquitin ligase. Although monocytes play an important role in tumor clearance, tumor cells can develop immune evasion. Acute Myeloid Leukemia (AML) is a hematologic malignancy caused by the proliferation of immature myeloid cells, which accumulate in the bone marrow, peripheral blood, and other tissues.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • One Target, Different Effects: a Comparison of Distinct Therapeutic Antibodies Against the Same Targets
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 43, No. 10, 539-549, October 2011 One target, different effects: a comparison of distinct therapeutic antibodies against the same targets Hyunbo Shim ple, four antibodies against TNF-α have been approved by the FDA -- infliximab, adalimumab, golimumab, and Department of Life Science certolizumab pegol -- with many more in clinical and Division of Life and Pharmaceutical Sciences preclinical development. The situation is similar for Ewha Womans University HER2, CD20, EGFR, and VEGF, each having one or Seoul 120-750, Korea more approved antibodies and many more under Correspondence: Tel, 82-2-3277-4240; development. This review discusses the different bind- Fax, 82-2-3277-3760; E-mail, [email protected] ing characteristics, mechanisms of action, and bio- http://dx.doi.org/10.3858/emm.2011.43.10.063 logical and clinical activities of multiple monoclonal antibodies against TNF-α, HER-2, CD20, and EGFR and Accepted 2 August 2011 provides insights into the development of therapeutic Available Online 3 August 2011 antibodies. Abbreviations: ADC, antibody-drug conjugate; ADCC, antibody- dependent cellular cytotoxicity; CD20, cluster of differentiation Keywords: antibodies, monoclonal; antigens, CD20; 20; CDC, complement dependent cytotoxicity; CLL, chronic pharmacology; receptor, epidermal growth factor; re- lymphocytic leukemia; ECD, extracellular domain; EGFR, epi- ceptor, erbB-2; tumor necrosis factor-α dermal growth factor receptor; EpCAM, epithelial cell adhe- sion molecule; FcγR, Fc gamma receptor;
    [Show full text]
  • Targeting the Function of the HER2 Oncogene in Human Cancer Therapeutics
    Oncogene (2007) 26, 6577–6592 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Targeting the function of the HER2 oncogene in human cancer therapeutics MM Moasser Department of Medicine, Comprehensive Cancer Center, University of California, San Francisco, CA, USA The year 2007 marks exactly two decades since human HER3 (erbB3) and HER4 (erbB4). The importance of epidermal growth factor receptor-2 (HER2) was func- HER2 in cancer was realized in the early 1980s when a tionally implicated in the pathogenesis of human breast mutationally activated form of its rodent homolog neu cancer (Slamon et al., 1987). This finding established the was identified in a search for oncogenes in a carcinogen- HER2 oncogene hypothesis for the development of some induced rat tumorigenesis model(Shih et al., 1981). Its human cancers. An abundance of experimental evidence human homologue, HER2 was simultaneously cloned compiled over the past two decades now solidly supports and found to be amplified in a breast cancer cell line the HER2 oncogene hypothesis. A direct consequence (King et al., 1985). The relevance of HER2 to human of this hypothesis was the promise that inhibitors of cancer was established when it was discovered that oncogenic HER2 would be highly effective treatments for approximately 25–30% of breast cancers have amplifi- HER2-driven cancers. This treatment hypothesis has led cation and overexpression of HER2 and these cancers to the development and widespread use of anti-HER2 have worse biologic behavior and prognosis (Slamon antibodies (trastuzumab) in clinical management resulting et al., 1989).
    [Show full text]
  • The Two Tontti Tudiul Lui Hi Ha Unit
    THETWO TONTTI USTUDIUL 20170267753A1 LUI HI HA UNIT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017 /0267753 A1 Ehrenpreis (43 ) Pub . Date : Sep . 21 , 2017 ( 54 ) COMBINATION THERAPY FOR (52 ) U .S . CI. CO - ADMINISTRATION OF MONOCLONAL CPC .. .. CO7K 16 / 241 ( 2013 .01 ) ; A61K 39 / 3955 ANTIBODIES ( 2013 .01 ) ; A61K 31 /4706 ( 2013 .01 ) ; A61K 31 / 165 ( 2013 .01 ) ; CO7K 2317 /21 (2013 . 01 ) ; (71 ) Applicant: Eli D Ehrenpreis , Skokie , IL (US ) CO7K 2317/ 24 ( 2013. 01 ) ; A61K 2039/ 505 ( 2013 .01 ) (72 ) Inventor : Eli D Ehrenpreis, Skokie , IL (US ) (57 ) ABSTRACT Disclosed are methods for enhancing the efficacy of mono (21 ) Appl. No. : 15 /605 ,212 clonal antibody therapy , which entails co - administering a therapeutic monoclonal antibody , or a functional fragment (22 ) Filed : May 25 , 2017 thereof, and an effective amount of colchicine or hydroxy chloroquine , or a combination thereof, to a patient in need Related U . S . Application Data thereof . Also disclosed are methods of prolonging or increasing the time a monoclonal antibody remains in the (63 ) Continuation - in - part of application No . 14 / 947 , 193 , circulation of a patient, which entails co - administering a filed on Nov. 20 , 2015 . therapeutic monoclonal antibody , or a functional fragment ( 60 ) Provisional application No . 62/ 082, 682 , filed on Nov . of the monoclonal antibody , and an effective amount of 21 , 2014 . colchicine or hydroxychloroquine , or a combination thereof, to a patient in need thereof, wherein the time themonoclonal antibody remains in the circulation ( e . g . , blood serum ) of the Publication Classification patient is increased relative to the same regimen of admin (51 ) Int .
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub
    US 20170172932A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0172932 A1 Peyman (43) Pub. Date: Jun. 22, 2017 (54) EARLY CANCER DETECTION AND A 6LX 39/395 (2006.01) ENHANCED IMMUNOTHERAPY A61R 4I/00 (2006.01) (52) U.S. Cl. (71) Applicant: Gholam A. Peyman, Sun City, AZ CPC .......... A61K 9/50 (2013.01); A61K 39/39558 (US) (2013.01); A61K 4I/0052 (2013.01); A61 K 48/00 (2013.01); A61K 35/17 (2013.01); A61 K (72) Inventor: sham A. Peyman, Sun City, AZ 35/15 (2013.01); A61K 2035/124 (2013.01) (21) Appl. No.: 15/143,981 (57) ABSTRACT (22) Filed: May 2, 2016 A method of therapy for a tumor or other pathology by administering a combination of thermotherapy and immu Related U.S. Application Data notherapy optionally combined with gene delivery. The combination therapy beneficially treats the tumor and pre (63) Continuation-in-part of application No. 14/976,321, vents tumor recurrence, either locally or at a different site, by filed on Dec. 21, 2015. boosting the patient’s immune response both at the time or original therapy and/or for later therapy. With respect to Publication Classification gene delivery, the inventive method may be used in cancer (51) Int. Cl. therapy, but is not limited to such use; it will be appreciated A 6LX 9/50 (2006.01) that the inventive method may be used for gene delivery in A6 IK 35/5 (2006.01) general. The controlled and precise application of thermal A6 IK 4.8/00 (2006.01) energy enhances gene transfer to any cell, whether the cell A 6LX 35/7 (2006.01) is a neoplastic cell, a pre-neoplastic cell, or a normal cell.
    [Show full text]
  • Advances in Systemic Therapy for HER2-Positive Metastatic Breast Cancer Phuong Khanh H Morrow1, Francisco Zambrana1,2 and Francisco J Esteva1
    Available online http://breast-cancer-research.com/content/11/4/207 Review Advances in systemic therapy for HER2-positive metastatic breast cancer Phuong Khanh H Morrow1, Francisco Zambrana1,2 and Francisco J Esteva1 1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Holcombe Boulevard, Houston, TX 77030, USA 2Current address: Department of Medical Oncology, Hospital Infanta Sofia, Paseo de Europa, 34, Madrid 28702, Spain Corresponding author: Phuong Khanh H Morrow, [email protected] Published: 15 July 2009 Breast Cancer Research 2009, 11:207 (doi:10.1186/bcr2324) This article is online at http://breast-cancer-research.com/content/11/4/207 © 2009 BioMed Central Ltd Abstract differentiation, survival, and migration that are associated with Human epidermal growth factor receptor (HER)2 over-expression HER2-positive breast cancers (Figure 1). Thus, women with is associated with a shortened disease-free interval and poor HER2-positive breast cancers exhibit significantly decreased survival. Although the addition of trastuzumab to chemotherapy in disease-free survival and overall survival (OS) [2-5]. the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastu- This review discusses progress in the treatment of HER2- zumab was used beyond the first-line setting because of multiple positive metastatic breast cancer since the discovery of the mechanisms of resistance. Studies have demonstrated the clinical utility of continuing
    [Show full text]
  • Monoclonal Antibodies in Cancer Therapy
    Clin Oncol Cancer Res (2011) 8: 215–219 215 DOI 10.1007/s11805-011-0583-7 Monoclonal Antibodies in Cancer Therapy Yu-Ting GUO1,2 ABSTRACT Monoclonal antibodies (MAbs) are a relatively new Qin-Yu HOU1,2 innovation in cancer treatment. At present, some monoclonal antibodies have increased the efficacy of the treatment of certain 1,2 Nan WANG tumors with acceptable safety profiles. When monoclonal antibodies enter the body and attach to cancer cells, they function in several different ways: first, they can trigger the immune system to attack and kill that cancer cell; second, they can block the growth signals; third, they can prevent the formation of new blood vessels. Some naked 1 Key Laboratory of Industrial Fermentation MAbs such as rituximab can be directed to attach to the surface of Microbiology, Ministry of Education, Tianjin, cancer cells and make them easier for the immune system to find and 300457, China. destroy. The ability to produce antibodies with limited immunogeni- 2 Tianjin Key Laboratory of Industrial Micro- city has led to the production and testing of a host of agents, several biology, College of Biotechnology, Tianjin of which have demonstrated clinically important antitumor activity University of Science and Technology, Tianjin, 300457, China. and have received U.S. Food & Drug Administration (FDA) approval as cancer treatments. To reduce the immunogenicity of murine anti- bodies, murine molecules are engineered to remove the immuno- genic content and to increase their immunologic efficiency. Radiolabeled antibodies composed of antibodies conjugated to radionuclides show efficacy in non-Hodgkin’s lymphoma. Anti- vascular endothelial growth factor (VEGF) antibodies such as bevacizumab intercept the VEGF signal of tumors, thereby stopping them from connecting with their targets and blocking tumor growth.
    [Show full text]
  • A Phase I Trial of the Trifunctional Anti Her2 × Anti CD3 Antibody Ertumaxomab in Patients with Advanced Solid Tumors N
    Haense et al. BMC Cancer (2016) 16:420 DOI 10.1186/s12885-016-2449-0 RESEARCH ARTICLE Open Access A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors N. Haense1†, A. Atmaca2†, C. Pauligk1, K. Steinmetz1, F. Marmé3, G. M. Haag3, M. Rieger4, O. G. Ottmann5, P. Ruf6, H. Lindhofer6 and S.-E. Al-Batran1* Abstract Background: Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells. Methods: Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10–500 μg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded. Results: Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14).
    [Show full text]
  • 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.
    [Show full text]