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A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors

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A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors Published OnlineFirst February 9, 2016; DOI: 10.1158/1078-0432.CCR-15-1696 Cancer Therapy: Preclinical Clinical Cancer Research A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors Marina Bacac1, Tanja Fauti1, Johannes Sam1, Sara Colombetti1, Tina Weinzierl1, Djamila Ouaret2, Walter Bodmer2, Steffi Lehmann3, Thomas Hofer4, Ralf J. Hosse4, Ekkehard Moessner4, Oliver Ast4, Peter Bruenker4, Sandra Grau-Richards4, Teilo Schaller1, Annette Seidl5, Christian Gerdes1, Mario Perro1, Valeria Nicolini1, Nathalie Steinhoff1, Sherri Dudal6, Sebastian Neumann7, Thomas von Hirschheydt8, Christiane Jaeger4, Jose Saro9, Vaios Karanikas9, Christian Klein1, and Pablo Umana~ 1 Abstract Purpose: CEA TCB is a novel IgG-based T-cell bispecific (TCB) strongly correlates with CEA expression, with higher potency ob- antibody for the treatment of CEA-expressing solid tumors cur- served in highly CEA-expressing tumor cells and a threshold of rently in phase I clinical trials (NCT02324257). Its format incor- approximately 10,000 CEA-binding sites/cell, which allows distin- porates bivalent binding to CEA, a head-to-tail fusion of CEA- and guishing between high- and low-CEA–expressing tumor and pri- CD3e-binding Fab domains and an engineered Fc region with mary epithelial cells, respectively. Genetic factors do not affect CEA completely abolished binding to FcgRs and C1q. The study TCB activity confirming that CEA expression level is the strongest provides novel mechanistic insights into the activity and mode predictor of CEA TCB activity. In vivo, CEA TCB induces regression of action of CEA TCB. of CEA-expressing xenograft tumors with variable amounts of Experimental Design: CEA TCB activity was characterized on immune cell infiltrate, leads to increased frequency of activated 110 cell lines in vitro and in xenograft tumor models in vivo T cells, and converts PD-L1 negative into PD-L1–positive tumors. using NOG mice engrafted with human peripheral blood Conclusions: CEA TCB is a novel generation TCB displaying mononuclear cells. potent antitumor activity; it is efficacious in poorly infiltrated Results: Simultaneous binding of CEA TCB to tumor and T cells tumors where it increases T-cell infiltration and generates leads to formation of immunologic synapses, T-cell activation, ahighlyinflamed tumor microenvironment. Clin Cancer Res; secretion of cytotoxic granules, and tumor cell lysis. CEA TCB activity 22(13); 3286–97. Ó2016 AACR. 1Oncology Discovery, Roche Innovation Center Zurich, Roche Phar- maceutical Research and Early Development, pRED, Zurich, Switzer- Introduction land. 2Cancer and Immunogenetics Laboratory,Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom. Redirecting the activity of T cells by bispecific antibodies 3Animal Imaging Center, Institute for Biomedical Engineering, ETH against tumor cells, independently of their TCR specificity, is a 4 and University of Zurich, Zurich, Switzerland. Large Molecule potent approach to treat cancer (reviewed in refs.1–3). The Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland. 5Roche concept is based on recognition of a cell surface tumor antigen Diagnostics GmbH, Penzberg, Germany. 6Pharmaceutical Sciences, and simultaneous binding to the CD3 epsilon chain (CD3e) 7 Roche Innovation Center Basel, Basel, Switzerland. Global Technical within the T-cell receptor (TCR) complex on T cells. This Development Project Management, F. Hoffmann-La Roche AG, Basel, Switzerland. 8Large Molecule Research, Roche Innovation Center triggers T-cell activation, including release of cytotoxic mole- Penzberg,Germany. 9Translational Medicine, Roche Innovation Center cules, cytokines and chemokines, and induction of T-cell pro- Zurich, Zurich, Switzerland. liferation (1, 2). Note: Supplementary data for this article are available at Clinical Cancer The first T-cell bispecific (TCB) antibody was described 30 Research Online (http://clincancerres.aacrjournals.org/). years ago (4), but it was only recently that the first TCB for C. Klein and P. Umana~ contributed equally to this article. systemic administration to cancer patients, blinatumomab, an  Corresponding Authors: Marina Bacac, Roche Pharma Research and Early anti-CD19 anti-CD3e TCB, was approved by the FDA for the Development, Roche Innovation Center Zurich, Wagistrasse 18, Schlieren, Zurich treatment of relapsed/refractory B-cell acute lymphocytic leu- 8952, Switzerland. Phone: 414-4755-6141; Fax: þ41 44 755 61 60; E-mail: kemia (B-ALL; ref. 5). A major limitation of the earlier TCB [email protected]; and Pablo Umana,~ Roche Pharma Research and Early molecules was that they induced strong cytokine release and Development, Roche Innovation Center Zurich,Wagistrasse 18, Schlieren, Zurich resulted in severe infusion-related reactions, which precluded þ 8952, Switzerland. Phone: 414-4755-6141; Fax: 41 44 755 61 60; E-mail: their systemic administration. Indeed such an earlier TCB, [email protected] catumaxomab, targeting EpCAM, could only be applied for doi: 10.1158/1078-0432.CCR-15-1696 local, peritoneal administration for the treatment of malignant Ó2016 American Association for Cancer Research. ascites (6). Besides being highly immunogenic in humans (as 3286 Clin Cancer Res; 22(13) July 1, 2016 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst February 9, 2016; DOI: 10.1158/1078-0432.CCR-15-1696 CEA TCB antibody targeting solid tumors protein that belongs to the CEACAM superfamily and is Translational Relevance anchored to the cell surface via glycosylphosphatidylinositol The study provides novel mechanistic insights into the (GPI). CEA expression in various tumor entities is generally design and activity of CEA TCB, an IgG-based T-cell bispe- very high, especially in colorectal carcinoma, pancreatic ade- cific antibody (TCB) currently in phase I clinical trials nocarcinoma, gastric cancer, non–smallcelllungcancerade- (NCT02324257). Its novel design confers long circulatory nocarcinoma (NSCLC), breast cancer, head and neck carcinoma half-life along with selective tumor targeting, intratumor (HNSCC), uterine and bladder cancers among others (9). T-cell activation and killing without peripheral blood Low expression is found in small-cell lung cancer and glioblas- immune cell activation. In addition to the novel molecular toma (10–15). CEA is expressed at low levels on the apical features of the TCB format, the article provides insights into surface of glandular epithelia in the gastrointestinal tract, interesting aspects related to the biologic activity of CEA but its polarized expression pattern limits accessibility to ther- TCB, including a threshold of CEA receptors required for apeutic antibodies administered systemically (10, 11, 16, 17). activity, selectivity for high CEA-expressing tumor cells, In addition to the novel molecular features of the TCB format, efficacy in non-inflamed and poorly T-cell–infiltrated the article provides insights into interesting aspects related tumors. and the ability to increase T-cell infiltration in to the biologic activity of CEA TCB, including a threshold of tumors, thus converting the non-inflamed, PD-L1–negative CEA receptors required for activity, selectivity for high CEA- tumors into highly inflamed and PD-L1–positive tumors expressing tumor cells, efficacy in non-inflamed and poorly resulting in the generation of a more inflamed tumor T-cell–infiltrated tumors and the ability to increase T-cell infil- microenvironment. trationintumors,thusgeneratingamoreinflamed tumor microenvironment. Materials and Methods rat/mouse hybrid monoclonal antibody), catumaxomab car- Cells, CEA expression level, and antibody binding ries an active Fc domain capable of crosslinking FcgRs on The list of all cell lines used in the study, their source and innate immune cells and CD3e on T cells, which leads to authentication is provided in Supplementary Table S1. The cell strong cytokine release upon systemic administration, inde- line panel (C10, C106, C10A, C10S, C125PM, C2BBe1, C32, pendently of tumor target cell binding (7). This limitation was C70, C75, C80, C99, CACO2, CAR1, CC20, CCK81, CCO7, overcome in blinatumomab by removing the Fc domain and CL11, CL14, CL40, COCM1, COLO201, COLO205, COLO206, linking the anti-CD19 and anti-CD3e domains via a short, COLO320DM, COLO320HSR, COLO678, CW2, CX1, DLD1, flexible Gly-Ser linker (3). However, by removing the Fc region, GP2d, GP5d, HCA46, HCA7, HCC2998, HCC56, HCT116, protection from catabolism via FcRn recycling was eliminated HCT15, HDC111, HDC114, HDC135, HDC142, HDC143, and this, together with the small molecular size of blinatu- HDC54, HDC57, HDC73, HDC8, HDC82, HDC9, HRA19, momab, leads to fast drug clearance. Indeed, blinatumomab HT29, HT55, ISRECO1, JHCOLOYI, JHSK-rec, KM20L2, has to be administered via continuous infusion for several LIM1215, LIM1863, LIM2405, LOVO, LS1034, LS123, LS174T, weeks (5), an approach which would significantly limit the LS180, LS411, LS513, NCIH508, NCIH548, NCIH716, application of TCBs to the majority of cancer patients. Thus, NCIH747, OUMS23, OXCO1, OXCO2, OXCO3, PCJW, new TCB molecular formats with comparable or higher efficacy PMFKO14, RCM1, RKO, RW2982, RW7213, SKCO1, SNU1181, than blinatumomab, but with significantly longer circulatory SNU1235, SNU1411, SNU1544, SNU1684, SNU1746, half-life allowing for systemic administration
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