The CEA/CD3-bispecific antibody MEDI-565 (MT111) binds a nonlinear epitope in the full-length but not a short splice variant of CEA

PLoS ONE

Volumn 7, Issue 5, 2012, Pages

  Peng, Li ^a   Oberst, Michael D ^a   Huang, Jiaqi ^a   Brohawn, Philip ^a   Morehouse, Chris ^a   Lekstrom, Kristen ^a   Baeuerle, Patrick A ^b   Wu, Herren ^a   Yao, Yihong ^a   Coats, Steven R ^a   Dall'Acqua, William ^a   Damschroder, Melissa ^a   Hammond, Scott A ^a  

^a MEDIMMUNE   (United States)

^b Amgen Research GmbH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; BISPECIFIC ANTIBODY; BISPECIFIC T CELL ENGAGER ANTIBODY; CARCINOEMBRYONIC ANTIBODY; CARCINOEMBRYONIC ANTIGEN; CD3 ANTIBODY; EPITOPE; MEDI 565; MESSENGER RNA; MT 111; UNCLASSIFIED DRUG; CD3 ANTIGEN; ISOPROTEIN; MONOCLONAL ANTIBODY;

AMINO TERMINAL SEQUENCE; ANTIGEN BINDING; ANTIGEN EXPRESSION; ANTIGEN RECOGNITION; ARTICLE; CANCER CELL; CELL KILLING; CONFORMATION; DATA BASE; DRUG TARGETING; EPITOPE MAPPING; HOMOZYGOSITY; HUMAN; HUMAN CELL; HUMAN TISSUE; MULTIPLE CANCER; MUTAGENESIS; NUCLEOTIDE SEQUENCE; PROTEIN DOMAIN; PROTEIN POLYMORPHISM; REAL TIME POLYMERASE CHAIN REACTION; SEQUENCE HOMOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM; T LYMPHOCYTE; ADULT; AGED; AMINO ACID SEQUENCE; ANIMAL; ANTIBODY SPECIFICITY; CELL STRAIN HEK293; CHEMICAL STRUCTURE; CHEMISTRY; CHO CELL; CRICETULUS; CYTOLOGY; GENE EXPRESSION REGULATION; GENETICS; HAMSTER; IMMUNOLOGY; METABOLISM; MIDDLE AGED; MOLECULAR GENETICS; MOUSE; NEOPLASM; PATHOLOGY; PROTEIN TERTIARY STRUCTURE;

ADULT; AGED; AMINO ACID SEQUENCE; ANIMALS; ANTIBODIES, BISPECIFIC; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTIBODY SPECIFICITY; ANTIGENS, CD3; CARCINOEMBRYONIC ANTIGEN; CHO CELLS; CRICETINAE; CRICETULUS; EPITOPE MAPPING; EPITOPES; GENE EXPRESSION REGULATION, NEOPLASTIC; HEK293 CELLS; HUMANS; MICE; MIDDLE AGED; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; NEOPLASMS; PROTEIN ISOFORMS; PROTEIN STRUCTURE, TERTIARY; RNA, MESSENGER; T-LYMPHOCYTES; YOUNG ADULT;

EID: 84860515259     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0036412     Document Type: Article

References (56)

1. Oikawa S, Nakazato H, Kosaki G, (1987) Primary structure of human carcinoembryonic antigen (CEA) deduced from cDNA sequence. Biochem Biophys Res Commun 142: 511-518.
2. Beauchemin N, Benchimol S, Cournoyer D, Fuks A, Stanners CP, (1987) Isolation and characterization of full-length functional cDNA clones for human carcinoembryonic antigen. Mol Cell Biol 7: 3221-3230.
3. Hammarstrom S, (1999) The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol 9: 67-81.
4. Kim HJ, Lee KW, Kim YJ, Oh DY, Kim JH, et al. (2009) Chemotherapy-induced transient CEA and CA19-9 surges in patients with metastatic or recurrent gastric cancer. Acta Oncol 48: 385-390.
5. Yamamoto M, Maehara Y, Sakaguchi Y, Mine H, Yamanaka T, et al. (2004) Distributions in CEA doubling time differ in patients with recurrent colorectal carcinomas. Hepatogastroenterology 51: 147-151.
6. Goldstein MJ, Mitchell EP, (2005) Carcinoembryonic antigen in the staging and follow-up of patients with colorectal cancer. Cancer Invest 23: 338-351.
7. Duffy MJ, (2001) Carcinoembryonic antigen as a marker for colorectal cancer: is it clinically useful? Clin Chem 47: 624-630.
8. Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, et al. (2006) ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 24: 5313-5327.
9. Rother M, (2007) Carcinoembryonic antigen monitoring for early detection of asymptomatic incurable metastatic colorectal cancer. J Clin Oncol 25: 1293-1294; author reply 1294.
10. Goldenberg DM, Wlodkowski TJ, Sharkey RM, Silberstein EB, Serafini AN, et al. (1993) Colorectal cancer imaging with iodine-123-labeled CEA monoclonal antibody fragments. J Nucl Med 34: 61-70.
11. Moffat FL Jr, Pinsky CM, Hammershaimb L, Petrelli NJ, Patt YZ, et al. (1996) Clinical utility of external immunoscintigraphy with the IMMU-4 technetium-99 m Fab' antibody fragment in patients undergoing surgery for carcinoma of the colon and rectum: results of a pivotal, phase III trial. The Immunomedics Study Group. J Clin Oncol 14: 2295-2305.
12. Hong H, Sun J, Cai W, (2008) Radionuclide-Based Cancer Imaging Targeting the Carcinoembryonic Antigen. Biomark Insights 3: 435-451.
13. Behr TM, Liersch T, Greiner-Bechert L, Griesinger F, Behe M, et al. (2002) Radioimmunotherapy of small-volume disease of metastatic colorectal cancer. Cancer 94: 1373-1381.
14. Huang EH, Kaufman HL, (2002) CEA-based vaccines. Expert Rev Vaccines 1: 49-63.
15. Francis RJ, Sharma SK, Springer C, Green AJ, Hope-Stone LD, et al. (2002) A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours. Br J Cancer 87: 600-607.
16. Lutterbuese R, Raum T, Kischel R, Lutterbuese P, Schlereth B, et al. (2009) Potent control of tumor growth by CEA/CD3-bispecific single-chain antibody constructs that are not competitively inhibited by soluble CEA. J Immunother 32: 341-352.
17. Osada T, Hsu D, Hammond S, Hobeika A, Devi G, et al. (2010) Metastatic colorectal cancer cells from patients previously treated with chemotherapy are sensitive to T-cell killing mediated by CEA/CD3-bispecific T-cell-engaging BiTE antibody. Br J Cancer 102: 124-133.
18. Fuhrmann S, Amann M, Mulgrew K, Lorenczewski G, Baffa R, et al. (2010) In vitro and in vivo pharmacology of MEDI-565 (MT111), a novel CEA/CD3-bispecific single-chain BiTE antibody for the treatment of gastrointestinal adenocarcinomas. AACR Meeting Abstracts abstract 5625.
19. Baeuerle PA, Reinhardt C, (2009) Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res 69: 4941-4944.
20. Brischwein K, Parr L, Pflanz S, Volkland J, Lumsden J, et al. (2007) Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J Immunother 30: 798-807.
21. Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA, (2005) BiTEs: bispecific antibody constructs with unique anti-tumor activity. Drug Discov Today 10: 1237-1244.
22. Mack M, Gruber R, Schmidt S, Riethmuller G, Kufer P, (1997) Biologic properties of a bispecific single-chain antibody directed against 17-1A (EpCAM) and CD3: tumor cell-dependent T cell stimulation and cytotoxic activity. J Immunol 158: 3965-3970.
23. Haas C, Krinner E, Brischwein K, Hoffmann P, Lutterbuse R, et al. (2009) Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology 214: 441-453.
24. Offner S, Hofmeister R, Romaniuk A, Kufer P, Baeuerle PA, (2006) Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells. Mol Immunol 43: 763-771.
25. Witthauer J, Schlereth B, Brischwein K, Winter H, Funke I, et al. (2009) Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110. Breast Cancer Res Treat 117: 471-481.
26. Brandl C, Haas C, d'Argouges S, Fisch T, Kufer P, et al. (2007) The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct. Cancer Immunol Immunother 56: 1551-1563.
27. Loffler A, Kufer P, Lutterbuse R, Zettl F, Daniel PT, et al. (2000) A recombinant bispecific single-chain antibody, CD19×CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 95: 2098-2103.
28. Kischel R, Hausmann S, Baeuerle P, Kufer P, (2009) Effector memory T cells make a major contribution to redirected target cell lysis by T cell-engaging BiTE antibody MT110. AACR Meeting Abstracts.
29. Mack M, Riethmuller G, Kufer P, (1995) A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc Natl Acad Sci U S A 92: 7021-7025.
30. Wimberger P, Xiang W, Mayr D, Diebold J, Dreier T, et al. (2003) Efficient tumor cell lysis by autologous, tumor-resident T lymphocytes in primary ovarian cancer samples by an EP-CAM-/CD3-bispecific antibody. Int J Cancer 105: 241-248.
31. Amann M, Friedrich M, Lutterbuese P, Vieser E, Lorenczewski G, et al. (2009) Therapeutic window of an EpCAM/CD3-specific BiTE antibody in mice is determined by a subpopulation of EpCAM-expressing lymphocytes that is absent in humans. Cancer Immunol Immunother 58: 95-109.
32. Amann M, Brischwein K, Lutterbuese P, Parr L, Petersen L, et al. (2008) Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3. Cancer Res 68: 143-151.
33. Dreier T, Baeuerle PA, Fichtner I, Grun M, Schlereth B, et al. (2003) T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct. J Immunol 170: 4397-4402.
34. Hammond SA, Lutterbuese R, Roff S, Lutterbuese P, Schlereth B, et al. (2007) Selective targeting and potent control of tumor growth using an EphA2/CD3-Bispecific single-chain antibody construct. Cancer Res 67: 3927-3935.
35. Herrmann I, Baeuerle PA, Friedrich M, Murr A, Filusch S, et al. (2010) Highly efficient elimination of colorectal tumor-initiating cells by an EpCAM/CD3-bispecific antibody engaging human T cells. PLoS One 5: e13474.
36. Schlereth B, Fichtner I, Lorenczewski G, Kleindienst P, Brischwein K, et al. (2005) Eradication of tumors from a human colon cancer cell line and from ovarian cancer metastases in immunodeficient mice by a single-chain Ep-CAM-/CD3-bispecific antibody construct. Cancer Res 65: 2882-2889.
37. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, et al. (2008) Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321: 974-977.
38. Topp MS, Kufer P, Gokbuget N, Goebeler M, Klinger M, et al. (2011) Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 29: 2493-2498.
39. Nagorsen D, Baeuerle PA, (2011) Immunomodulatory therapy of cancer with T cell-engaging BiTE antibody blinatumomab. Exp Cell Res 317: 1255-1260.
40. Harwood PJ, Britton DW, Southall PJ, Boxer GM, Rawlins G, et al. (1986) Mapping epitope characteristics on carcinoembryonic antigen. Br J Cancer 54: 75-82.
41. Chester KA, Robson L, Keep PA, Pedley RB, Boden JA, et al. (1994) Production and tumour-binding characterization of a chimeric anti-CEA Fab expressed in Escherichia coli. Int J Cancer 57: 67-72.
42. Boxer GM, Abassi AM, Pedley RB, Begent RH, (1994) Localisation of monoclonal antibodies reacting with different epitopes on carcinoembryonic antigen (CEA)-implications for targeted therapy. Br J Cancer 69: 307-314.
43. Arnold K, Bordoli L, Kopp J, Schwede T, (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22: 195-201.
44. Tan K, Zelus BD, Meijers R, Liu JH, Bergelson JM, et al. (2002) Crystal structure of murine sCEACAM1a[1,4]: a coronavirus receptor in the CEA family. EMBO J 21: 2076-2086.
45. Hefta SA, Hefta LJ, Lee TD, Paxton RJ, Shively JE, (1988) Carcinoembryonic antigen is anchored to membranes by covalent attachment to a glycosylphosphatidylinositol moiety: identification of the ethanolamine linkage site. Proc Natl Acad Sci U S A 85: 4648-4652.
46. Oikawa S, Imajo S, Noguchi T, Kosaki G, Nakazato H, (1987) The carcinoembryonic antigen (CEA) contains multiple immunoglobulin-like domains. Biochem Biophys Res Commun 144: 634-642.
47. Hampton R, Walker M, Marshall J, Juhl H, (2002) Differential expression of carcinoembryonic antigen (CEA) splice variants in whole blood of colon cancer patients and healthy volunteers: implication for the detection of circulating colon cancer cells. Oncogene 21: 7817-7823.
48. Zhou H, Fuks A, Alcaraz G, Bolling TJ, Stanners CP, (1993) Homophilic adhesion between Ig superfamily carcinoembryonic antigen molecules involves double reciprocal bonds. J Cell Biol 122: 951-960.
49. Schwarz K, Mehnert-Solzer C, von Kleist S, Grunert F, (1988) Analysis of the specificity of CEA reactive monoclonal antibodies. Immunological support for the domain-model of CEA. Mol Immunol 25: 889-898.
50. Hammarstrom S, Shively JE, Paxton RJ, Beatty BG, Larsson A, et al. (1989) Antigenic sites in carcinoembryonic antigen. Cancer Res 49: 4852-4858.
51. Hass GM, Bolling TJ, Kinders RJ, Henslee JG, Mandecki W, et al. (1991) Preparation of synthetic polypeptide domains of carcinoembryonic antigen and their use in epitope mapping. Cancer Res 51: 1876-1882.
52. Bjerner J, Lebedin Y, Bellanger L, Kuroki M, Shively JE, et al. (2002) Protein epitopes in carcinoembryonic antigen. Report of the ISOBM TD8 workshop. Tumour Biol 23: 249-262.
53. Murakami M, Kuroki M, Arakawa F, Kuwahara M, Oikawa S, et al. (1995) A reference of the GOLD classification of monoclonal antibodies against carcinoembryonic antigen to the domain structure of the carcinoembryonic antigen molecule. Hybridoma 14: 19-28.
54. Kaplan BE, Hefta LJ, Blake RC 2nd, Swiderek KM, Shively JE, (1998) Solid-phase synthesis and characterization of carcinoembryonic antigen (CEA) domains. J Pept Res 52: 249-260.
55. Solassol I, Granier C, Pelegrin A, (2001) Carcinoembryonic antigen continuous epitopes determined by the spot method. Tumour Biol 22: 184-190.
56. Nap M, Hammarstrom ML, Bormer O, Hammarstrom S, Wagener C, et al. (1992) Specificity and affinity of monoclonal antibodies against carcinoembryonic antigen. Cancer Res 52: 2329-2339.