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Solitomab, an Epcam/CD3 Bispecific Antibody Construct (Bite®), Is Ferrari et al. Journal of Experimental & Clinical Cancer Research (2015) 34:123 DOI 10.1186/s13046-015-0241-7 RESEARCH Open Access Solitomab, an EpCAM/CD3 bispecific antibody construct (BiTE®), is highly active against primary uterine and ovarian carcinosarcoma cell lines in vitro Francesca Ferrari1, Stefania Bellone1, Jonathan Black1, Carlton L. Schwab1, Salvatore Lopez1, Emiliano Cocco1, Elena Bonazzoli1, Federica Predolini1, Gulden Menderes1, Babak Litkouhi1, Elena Ratner1, Dan-Arin Silasi1, Masoud Azodi1, Peter E. Schwartz1 and Alessandro D. Santin1,2* Abstract Background: Uterine and ovarian carcinosarcomas (CS) are rare but highly aggressive gynecologic tumors which carry an extremely poor prognosis. We evaluated the expression levels of EpCAM and the in vitro activity of solitomab, a bispecific single-chain antibody construct which targets epithelial-cell-adhesion-molecule (EpCAM) on tumor cells and also contains a CD3 binding region, against primary uterine and ovarian CS cell lines. Methods: EpCAM expression was evaluated by flow cytometry in a total of 5 primary CS cell lines. Sensitivity to solitomab-dependent-cellular-cytotoxicity (ADCC) was tested against the panel of primary CS cell lines expressing different levels of EpCAM in standard 4 h 51Cr release-assays. The proliferative activity, activation, cytokine secretion (i.e., Type I vs Type II) and cytotoxicity of solitomab in autologous tumor-associated-T cells (TAL) in the pleural fluid of a CS patient were also evaluated by CFSE and flow-cytometry assays. Results: Surface expression of EpCAM was found in 80.0 % (4 out of 5) of the CS cell lines tested by flow cytometry. EpCAM positive cell lines were found resistant to NK or T-cell-mediated killing after exposure to peripheral blood lymphocytes (PBL) in 4-h chromium-release assays (mean killing ± SEM = 1.1 ± 1.6 %, range 0–5.3 % after incubation of EpCAM positive cell lines with control BiTE®). In contrast, after incubation with solitomab, EpCAM positive CS cells became highly sensitive to T-cell-cytotoxicity (mean killing ± SEM of 19.7 ± 6.3 %; range 10.0-32.0 %; P < 0.0001). Ex vivo incubation of autologous TAL with EpCAM expressing malignant cells in pleural effusion with solitomab, resulted in a significant increase in T-cell proliferation in both CD4+ and CD8+ T cells, increase in T-cell activation markers (i.e., CD25 and HLA-DR), and a reduction in number of viable CS cells in the exudate (P <0.001). Conclusions: Solitomab may represent an effective treatment for patients with recurrent/metastatic and/or chemo- resistant CS overexpressing EpCAM. Keywords: EpCAM, CD3, T-lymphocyte, Bispecific antibody, Uterine carcinosarcoma, Ovarian carcinosarcoma * Correspondence: [email protected] 1Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA 2333 Cedar Street, LSOG 305, PO Box 208063, New Haven, CT 06520-8063, USA © 2015 Ferrari et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ferrari et al. Journal of Experimental & Clinical Cancer Research (2015) 34:123 Page 2 of 8 Introduction expression in primary carcinosarcomas cell lines and ex- Gynecological carcinosarcomas (CS), also known as plored for the first time the potential of solitomab, an Malignant Mixed Mullerian Tumors (MMMT), are rare EpCAM/CD3 BiTE®, as a novel therapeutic strategy biphasic tumors that most commonly arise in the uterus against carcinosarcoma cell lines and un-manipulated and ovaries [1]. Histologically, the carcinomatous compo- malignant tumor cells isolated from malignant pleural nent may include endometrioid, serous, clear cell, fluid of a patient. Our results demonstrate impressive squamous or mucinous differentiation or may be undiffer- solitomab antitumor activity against carcinosarcoma cell entiated. CS are classified on the basis of the nature of lines and tumor cells in pleural fluid from patients with their mesenchymal elements as "homologous" when mes- gynecologic carcinosarcomas. enchymal components differentiate towards tissues physiologically native to the primary site (e.g. leiomyosar- Methods coma, fibrosarcoma and endometrial stromal sarcoma), or Patients and sample processing as “heterologous” when they contain mesenchymal com- All patients signed an informed consent form according ponents that are physiologically foreign to the primary site to institutional guidelines and approval for this in vitro (e.g. chondrosarcoma, osteosarcoma, rhabdomyosarcoma study was obtained from the institutional review board. A and liposarcoma). While the pathogenesis of CS remains total of five primary carcinoma cell lines [i.e., two primary under debate, an increasing body of evidence supports the uterine carcinosarcoma cell lines (SARARK-1 and origin of both elements from a common epithelial cell that SARARK-9) and three primary ovarian carcinosarcoma undergoes sarcomatous dedifferentiation, rather than two cell lines (SARARK-3, SARARK-6 and SARARK-7)] were independent progenitors [2–5]. While CS comprise only a established after sterile processing of surgical biopsy speci- small percentage (i.e., 1 to 5 %) of ovarian and uterine can- mens, as described previously [9]. Briefly, tumor tissue cers, the overall 5 year survival for ovarian and uterine CS was mechanically minced to portions no larger than 1 to patient remains a dismal 24 % and 36 %, respectively [1]. 3 mm3 in an enzyme solution made of 0.14 % collagenase The discovery of novel diagnostic and therapeutic markers type I (Sigma) and 0.01 % DNase (Sigma, 2000 KU/mg) in against this aggressive subset of gynecological tumors re- RPMI 1640, and incubated in the same solution in a mag- mains a high priority. netic stirring apparatus for an hour at room temperature. Overexpression of epithelial cell adhesion molecule-1 Enzymatically dissociated cells were then washed twice in (EpCAM), also known as TROP-1 or TACSTD1, is a RPMI 1640 with 10 % fetal bovine serum and maintained known poor prognostic biomarker across a large number in RPMI supplemented with 10 % fetal bovine serum, of carcinomas and carcinosarcomas [4, 5]. EpCAM, a 39 200 μg/ml of penicillin and 200 μg/ml of streptomycin at to 42 kd protein, consists of three domains including; an 37 °C, 5 % CO2 in 75 cm2 tissue culture flasks or Petri extracellular domain with 2 epidermal growth factor-like dishes (Corning). After seeding on plasticware for 48–72 repeats, a transmembrane domain, and a short 26 amino h, nonadherent cells and contaminant inflammatory cells acid cytoplasmic domain. EpCAM promotes cell adhe- were gently removed from the culture by multiple wash- sion and is expressed at low levels on different various ings with PBS. Both primary uterine carcinosarcoma cell epithelia. It is predominantly expressed in the basolateral lines were established from biopsies of the uterus of and intercellular surface of simple, pseudo-stratified, and chemotherapy naïve patients at the time of the primary transitional epithelia as well as most epithelial tissues in staging surgery, while all primary ovarian carcinosarcoma the female genital tract [6]. EpCAM is known to play an cell lines were obtained from the biopsy of metastatic sites important role in multiple cell functions including cell of disease in patients harboring recurrent, chemotherapy- migration, cell signaling, differentiation, and prolifera- resistant disease. In all primary ovarian carcinosarcoma tion. High levels of expression on the cell surface of cell lines cases, the high in vivo resistance to multiple multiple human carcinomas makes EpCAM an attractive chemotherapy agents was confirmed in vitro by MTT target for immunotherapy [7]. The discovery of EpCAM chemotherapy resistance assays against multiple cytotoxic (CD326) expression in a number of solid tumors led to agents (data not shown). Primary carcinosarcoma cell the development of Solitomab (MT110, AMG 110) lines were tested for presence of EpCAM by Quantitative which is an EpCAM/CD3-bispecific single-chain anti- Real-time PCR and by flow cytometry as described below. body construct [8]. Solitomab acts by engaging resting An additional tumor sample was collected from a CS pa- polyclonal CD8+ and CD4+ T cells for highly potent tient with recurrent disease and a large pleural effusion. redirected lysis of target tumor cells that express The fluid sample was cytologically confirmed to contain a EpCAM. Solitomab’s antitumor activity in preclinical large number of EpCAM + carcinosarcoma cells at the EpCAM positive ovarian tumor xenograft models has time of a therapeutic thoracentesis. The fresh sample of shown promise. In the current study, we have used flow pleural fluid was plated into 6-well microtiter plate for cytometry and q-Real-time-PCR to evaluate EpCAM treatment using solitomab and a nonspecific BiTE® control Ferrari et al. Journal of Experimental & Clinical Cancer Research (2015) 34:123 Page 3 of 8 antibody construct without prior processing. Cell numbers (Applied Biosystems) to evaluate
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