Anti-tumoral, anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2

mAbs

Volumn 8, Issue 3, 2016, Pages 562-573

  Scheuer, Werner ^a   Thomas, Markus ^a   Hanke, Petra ^a   Sam, Johannes ^b   Osl, Franz ^a   Weininger, Diana ^a   Baehner, Monika ^a   Seeber, Stefan ^a   Kettenberger, Hubert ^a   Schanzer, Jürgen ^a   Brinkmann, Ulrich ^a   Weidner, K Michael ^a   Regula, Jörg ^a   Klein, Christian ^b  

^a ROCHE INNOVATION CENTER MUNICH   (Germany)

^b Roche Pharma Research and Early Development   (Switzerland)

Author keywords

Angiopoietin 2; bispecific; BsAb; scFv; VEGF A

Indexed keywords

ANGIOGENESIS INHIBITOR; ANGIOPOIETIN 2; ANTIBODY; ANTIMETASTATIC AGENT; BEVACIZUMAB; CD31 ANTIBODY; SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY; SINGLE CHAIN FRAGMENT VARIABLE ANTIBODY LC06; TETRAVALENT BISPECIFIC ANTIBODY TAVI6; UNCLASSIFIED DRUG; VASCULOTROPIN A; VASCULOTROPIN RECEPTOR; ANGPT2 PROTEIN, HUMAN; BISPECIFIC ANTIBODY; CANCER ANTIBODY; TUMOR PROTEIN; VEGFA PROTEIN, HUMAN;

ANGIOGENESIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CELL PROLIFERATION ASSAY; CELL VIABILITY; CONTROLLED STUDY; CORNEAL MICROPOCKET MODEL; ENZYME LINKED IMMUNOSORBENT ASSAY; FEMALE; FLUORESCENCE MICROSCOPY; HISTOLOGY; HUMAN; HUMAN CELL; METASTASIS INHIBITION; MODEL; MOUSE; NEAR INFRARED IMAGING SYSTEM; NONHUMAN; PHOTON CORRELATION SPECTROSCOPY; POLYACRYLAMIDE GEL ELECTROPHORESIS; PROTEIN PURIFICATION; SIZE EXCLUSION CHROMATOGRAPHY; TRANSIENT TRANSFECTION; TUMOR XENOGRAFT; ANIMAL; ANTAGONISTS AND INHIBITORS; CHO CELL LINE; CRICETULUS; DRUG SCREENING; HAMSTER; HEK293 CELL LINE; IMMUNOLOGY; METASTASIS; NEOPLASMS, EXPERIMENTAL; NEOVASCULARIZATION, PATHOLOGIC; PATHOLOGY; UMBILICAL VEIN ENDOTHELIAL CELL;

ANGIOPOIETIN-2; ANIMALS; ANTIBODIES, BISPECIFIC; ANTIBODIES, NEOPLASM; CHO CELLS; CRICETINAE; CRICETULUS; HEK293 CELLS; HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS; HUMANS; MICE; NEOPLASM METASTASIS; NEOPLASM PROTEINS; NEOPLASMS, EXPERIMENTAL; NEOVASCULARIZATION, PATHOLOGIC; VASCULAR ENDOTHELIAL GROWTH FACTOR A; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84961644349     PISSN: 19420862     EISSN: 19420870     Source Type: Journal    
DOI: 10.1080/19420862.2016.1147640     Document Type: Article

References (42)

1. G.Bergers, D.Hanahan. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8(8):592-603; PMID:18650835; http://dx.doi.org/10.1038/nrc2442
2. Y.Crawford, N.Ferrara. Vegf inhibition: Insights from preclinical and clinical studies. Cell Tissue Res 2009; 335(1):261-9; PMID:18766380; http://dx.doi.org/10.1007/s00441-008-0675-8
3. F.S.Hodi, D.Lawrence, C.Lezcano, X.Wu, J.Zhou, T.Sasada, W.Zeng, A.Giobbie-Hurder, M.B.Atkins, N.Ibrahim, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2014; 2(7):632-42; PMID:24838938; http://dx.doi.org/10.1158/2326-6066.CIR-14-0053
4. J.Ma, D.J.Waxman. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Mol Cancer Ther 2008; 7(12):3670-84; PMID:19074844; http://dx.doi.org/10.1158/1535-7163.MCT-08-0715
5. A.M.Jubb, A.L.Harris. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol 2010; 11(12):1172-83; PMID:21126687; http://dx.doi.org/10.1016/S1470-2045(10)70232-1
6. N.T.Fernando, M.Koch, C.Rothrock, L.K.Gollogly, P.A.D'Amore, S.Ryeom, S.S.Yoon. Tumor escape from endogenous, extracellular matrix-associated angiogenesis inhibitors by up-regulation of multiple proangiogenic factors. Clin Cancer Res 2008; 14(5):1529-39; PMID:18316578; http://dx.doi.org/10.1158/1078-0432.CCR-07-4126
7. C.Daly, A.Eichten, C.Castanaro, E.Pasnikowski, A.Adler, A.S.Lalani, N.Papadopoulos, A.H.Kyle, A.I.Minchinton, G.D.Yancopoulos, et al. Angiopoietin-2 functions as a tie2 agonist in tumor models, where it limits the effects of vegf inhibition. Cancer Res 2013; 73(1):108-18; PMID:23149917; http://dx.doi.org/10.1158/0008-5472.CAN-12-2064
8. Y.Kienast, C.Klein, W.Scheuer, R.Raemsch, E.Lorenzon, D.Bernicke, F.Herting, S.Yu, H.H.The, L.Martarello, et al. Ang-2-vegf-a crossmab, a novel bispecific human igg1 antibody blocking vegf-a and ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin Cancer Res 2013; 19(24):6730-40; PMID:24097868; http://dx.doi.org/10.1158/1078-0432.CCR-13-0081
9. A.Scholz, P.N.Harter, S.Cremer, B.H.Yalcin, S.Gurnik, M.Yamaji, M.Di Tacchio, K.Sommer, P.Baumgarten, O.Bahr, et al. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol Med 2015; 8(1):39-57; PMID:26666269; http://dx.doi.org/10.15252/emmm.201505505
10. L.Xu, D.G.Duda, E.di Tomaso, M.Ancukiewicz, D.C.Chung, G.Y.Lauwers, R.Samuel, P.Shellito, B.G.Czito, P.C.Lin, et al. Direct evidence that bevacizumab, an anti-vegf antibody, up-regulates sdf1alpha, cxcr4, cxcl6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res 2009; 69(20):7905-10; PMID:19826039; http://dx.doi.org/10.1158/0008-5472.CAN-09-2099
11. J.L.Brown, Z.A.Cao, M.Pinzon-Ortiz, J.Kendrew, C.Reimer, S.Wen, J.Q.Zhou, M.Tabrizi, S.Emery, B.McDermott, et al. A human monoclonal anti-ang2 antibody leads to broad antitumor activity in combination with vegf inhibitors and chemotherapy agents in preclinical models. Mol Cancer Ther 2010; 9(1):145-56; PMID:20053776; http://dx.doi.org/10.1158/1535-7163.MCT-09-0554
12. H.Huang, J.Y.Lai, J.Do, D.Liu, L.Li, J.Del Rosario, V.R.Doppalapudi, S.Pirie-Shepherd, N.Levin, C.Bradshaw, et al. Specifically targeting angiopoietin-2 inhibits angiogenesis, tie2-expressing monocyte infiltration, and tumor growth. Clin Cancer Res 2011; 17(5):1001-11; PMID:21233403; http://dx.doi.org/10.1158/1078-0432.CCR-10-2317
13. C.C.Leow, K.Coffman, I.Inigo, S.Breen, M.Czapiga, S.Soukharev, N.Gingles, N.Peterson, C.Fazenbaker, R.Woods, et al. Medi3617, a human anti-angiopoietin 2 monoclonal antibody, inhibits angiogenesis and tumor growth in human tumor xenograft models. Int J Oncol 2012; 40(5):1321-30; PMID:22327175; http://dx.doi.org/10.3892/ijo.2012.1366
14. K.P.Papadopoulos, R.K.Kelley, A.W.Tolcher, A.R.Razak, K.Van Loon, A.Patnaik, P.L.Bedard, A.A.Alfaro, M.Beeram, L.Adriaens, et al. A phase i first-in-human study of nesvacumab (regn910), a fully human anti-angiopoietin-2 (ang2) monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res 2015; PMID:26490310
15. R.Mazzieri, F.Pucci, D.Moi, E.Zonari, A.Ranghetti, A.Berti, L.S.Politi, B.Gentner, J.L.Brown, L.Naldini, et al. Targeting the ang2/tie2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 2011; 19(4):512-26; PMID:21481792; http://dx.doi.org/10.1016/j.ccr.2011.02.005
16. J.Oliner, H.Min, J.Leal, D.Yu, S.Rao, E.You, X.Tang, H.Kim, S.Meyer, S.J.Han, et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell 2004; 6(5):507-16; PMID:15542434; http://dx.doi.org/10.1016/j.ccr.2004.09.030
17. M.Thomas, Y.Kienast, W.Scheuer, M.Bahner, K.Kaluza, C.Gassner, F.Herting, U.Brinkmann, S.Seeber, A.Kavlie, et al. A novel angiopoietin-2 selective fully human antibody with potent anti-tumoral and anti-angiogenic efficacy and superior side effect profile compared to pan-angiopoietin-1/-2 inhibitors. PLoS One 2013; 8(2):e54923; PMID:23405099; http://dx.doi.org/10.1371/journal.pone.0054923
18. D.Gerald, S.Chintharlapalli, H.G.Augustin, L.E.Benjamin. Angiopoietin-2: An attractive target for improved antiangiogenic tumor therapy. Cancer Res 2013; 73(6):1649-57; PMID:23467610; http://dx.doi.org/10.1158/0008-5472.CAN-12-4697
19. H.Hashizume, B.L.Falcon, T.Kuroda, P.Baluk, A.Coxon, D.Yu, J.V.Bready, J.D.Oliner, D.M.McDonald. Complementary actions of inhibitors of angiopoietin-2 and vegf on tumor angiogenesis and growth. Cancer Res 2010; 70(6):2213-23; PMID:20197469; http://dx.doi.org/10.1158/0008-5472.CAN-09-1977
20. V.R.Doppalapudi, J.Huang, D.Liu, P.Jin, B.Liu, L.Li, J.Desharnais, C.Hagen, N.J.Levin, M.J.Shields, et al. Chemical generation of bispecific antibodies. Proc Natl Acad Sci U S A 2010; 107(52):22611-16; PMID:21149738; http://dx.doi.org/10.1073/pnas.1016478108
21. J.M.Ebos, C.R.Lee, W.Cruz-Munoz, G.A.Bjarnason, J.G.Christensen, R.S.Kerbel. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009; 15(3):232-9; PMID:19249681; http://dx.doi.org/10.1016/j.ccr.2009.01.021
22. S.Loges, M.Mazzone, P.Hohensinner, P.Carmeliet. Silencing or fueling metastasis with vegf inhibitors: Antiangiogenesis revisited. Cancer Cell 2009; 15(3):167-70; PMID:19249675; http://dx.doi.org/10.1016/j.ccr.2009.02.007
23. M.Paez-Ribes, E.Allen, J.Hudock, T.Takeda, H.Okuyama, F.Vinals, M.Inoue, G.Bergers, D.Hanahan, O.Casanovas. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15(3):220-31; PMID:19249680; http://dx.doi.org/10.1016/j.ccr.2009.01.027
24. M.J.Coloma, S.L.Morrison. Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol 1997; 15(2):159-63; PMID:9035142; http://dx.doi.org/10.1038/nbt0297-159
25. Y.Reiter, U.Brinkmann, R.J.Kreitman, S.H.Jung, B.Lee, I.Pastan. Stabilization of the fv fragments in recombinant immunotoxins by disulfide bonds engineered into conserved framework regions. Biochemistry 1994; 33(18):5451-59; PMID:7910034; http://dx.doi.org/10.1021/bi00184a014
26. Y.Reiter, U.Brinkmann, K.O.Webber, S.H.Jung, B.Lee, I.Pastan. Engineering interchain disulfide bonds into conserved framework regions of fv fragments: Improved biochemical characteristics of recombinant immunotoxins containing disulfide-stabilized fv. Protein Eng 1994; 7(5):697-704; PMID:8073039; http://dx.doi.org/10.1093/protein/7.5.697
27. S.Metz, A.K.Haas, K.Daub, R.Croasdale, J.Stracke, W.Lau, G.Georges, H.P.Josel, S.Dziadek, K.P.Hopfner, et al. Bispecific digoxigenin-binding antibodies for targeted payload delivery. Proc Natl Acad Sci U S A 2011; 108(20):8194-99; PMID:21536919; http://dx.doi.org/10.1073/pnas.1018565108
28. R.Croasdale, K.Wartha, J.M.Schanzer, K.P.Kuenkele, C.Ries, K.Mayer, C.Gassner, M.Wagner, N.Dimoudis, S.Herter, et al. Development of tetravalent igg1 dual targeting igf-1r-egfr antibodies with potent tumor inhibition. Arch Biochem Biophys 2012; 526(2):206-18; PMID:22464987; http://dx.doi.org/10.1016/j.abb.2012.03.016
29. J.Schanzer, A.Jekle, J.Nezu, A.Lochner, R.Croasdale, M.Dioszegi, J.Zhang, E.Hoffmann, W.Dormeyer, J.Stracke, et al. Development of tetravalent, bispecific ccr5 antibodies with antiviral activity against ccr5 monoclonal antibody-resistant hiv-1 strains. Antimicrob Agents Chemother 2011; 55(5):2369-78; PMID:21300827; http://dx.doi.org/10.1128/AAC.00215-10
30. W.C.Liang, X.Wu, F.V.Peale, C.V.Lee, Y.G.Meng, J.Gutierrez, L.Fu, A.K.Malik, H.P.Gerber, N.Ferrara, et al. Cross-species vascular endothelial growth factor (vegf)-blocking antibodies completely inhibit the growth of human tumor xenografts and measure the contribution of stromal vegf. J Biol Chem 2006; 281(2):951-61; PMID:16278208; http://dx.doi.org/10.1074/jbc.M508199200
31. W.Schaefer, J.T.Regula, M.Bahner, J.Schanzer, R.Croasdale, H.Durr, C.Gassner, G.Georges, H.Kettenberger, S.Imhof-Jung, et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific igg antibodies. Proc Natl Acad Sci U S A 2011; 108(27):11187-92; PMID:21690412; http://dx.doi.org/10.1073/pnas.1019002108
32. N.Rigamonti, E.Kadioglu, I.Keklikoglou, C.Wyser Rmili, C.C.Leow, M.De Palma. Role of angiopoietin-2 in adaptive tumor resistance to vegf signaling blockade. Cell Rep 2014; 8(3):696-706; PMID:25088418; http://dx.doi.org/10.1016/j.celrep.2014.06.059
33. A.Kadenhe-Chiweshe, J.Papa, K.W.McCrudden, J.Frischer, J.O.Bae, J.Huang, J.Fisher, J.H.Lefkowitch, N.Feirt, J.Rudge, et al. Sustained vegf blockade results in microenvironmental sequestration of vegf by tumors and persistent vegf receptor-2 activation. Mol Cancer Res 2008; 6(1):1-9; PMID:18234958; http://dx.doi.org/10.1158/1541-7786.MCR-07-0101
34. W.C.Dempke, R.Zippel. Brivanib, a novel dual vegf-r2/bfgf-r inhibitor. Anticancer Res 2010; 30(11):4477-83; PMID:21115896
35. N.Zaghloul, S.L.Hernandez, J.O.Bae, J.Huang, J.C.Fisher, A.Lee, A.Kadenhe-Chiweshe, J.J.Kandel, D.J.Yamashiro. Vascular endothelial growth factor blockade rapidly elicits alternative proangiogenic pathways in neuroblastoma. Int J Oncol 2009; 34(2):401-7; PMID:19148474; http://dx.doi.org/10.3892/ijo_00000163
36. N.Rigamonti, M.De Palma. A role for angiopoietin-2 in organ-specific metastasis. Cell Rep 2013; 4(4):621-3; PMID:23993444; http://dx.doi.org/10.1016/j.celrep.2013.07.034
37. K.Srivastava, J.Hu, C.Korn, S.Savant, M.Teichert, S.S.Kapel, M.Jugold, E.Besemfelder, M.Thomas, M.Pasparakis, et al. Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 2014; 26(6):880-95; PMID:25490450; http://dx.doi.org/10.1016/j.ccell.2014.11.005
38. D.Keskin, J.Kim, V.G.Cooke, C.C.Wu, H.Sugimoto, C.Gu, M.De Palma, R.Kalluri, V.S.LeBleu. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep 2015; 10(7):1066-81; PMID:25704811; http://dx.doi.org/10.1016/j.celrep.2015.01.035
39. M.S.Rogers, A.E.Birsner, R.J.D'Amato. The mouse cornea micropocket angiogenesis assay. Nat Protoc 2007; 2(10):2545-50; PMID:17947997; http://dx.doi.org/10.1038/nprot.2007.368
40. J.Kurebayashi, T.Otsuki, C.K.Tang, M.Kurosumi, S.Yamamoto, K.Tanaka, M.Mochizuki, H.Nakamura, H.Sonoo. Isolation and characterization of a new human breast cancer cell line, kpl-4, expressing the erb b family receptors and interleukin-6. Br J Cancer 1999; 79(5-6):707-17; PMID:10070858; http://dx.doi.org/10.1038/sj.bjc.6690114
41. T.Schneider, F.Osl, T.Friess, H.Stockinger, W.V.Scheuer. Quantification of human alu sequences by real-time pcr–an improved method to measure therapeutic efficacy of anti-metastatic drugs in human xenotransplants. Clin Exp Metastasis 2002; 19(7):571-82; PMID:12498386; http://dx.doi.org/10.1023/A:1020992411420
42. E.Fieller. Some problems in interval estimation. J Royal Stat Soc 1954; B16; 16:2