Rationale and development of multispecific antibody drugs

Expert Review of Clinical Pharmacology

Volumn 3, Issue 4, 2010, Pages 491-508

  Gu, Jijie ^a   Ghayur, Tariq ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

bispecific antibodies; bispecific T cell engager; BiTE; bsAbs; dual variable domain Ig; DVD Ig; mAbs; monoclonal antibodies; retargeting; site specific targeting; Triomab

Indexed keywords

ABT 874; BISPECIFIC ANTIBODY; BLINATUMOMAB; CATUMAXOMAB; ERTUMAXOMAB; LYMPHOMUN; MEDI 438; MEDI 538; MT 110; REMOVAB; RITUXIMAB; TISSUE PLASMINOGEN ACTIVATOR; TRASTUZUMAB; TRIOMAB; UNCLASSIFIED DRUG; USTEKINUMAB;

ACUTE LYMPHOBLASTIC LEUKEMIA; BREAST CANCER; CLINICAL TRIAL; COMPLEMENT DEPENDENT CYTOTOXICITY; COMPLEMENTARITY DETERMINING REGION; CROSS LINKING; CYTOKINE RELEASE; CYTOKINE RELEASE SYNDROME; EFFECTOR CELL; HUMAN; IMMUNOGENICITY; IN VITRO STUDY; LEUKOPENIA; NONHODGKIN LYMPHOMA; OLIGOMERIZATION; REVIEW; THROMBOCYTOPENIA; TREATMENT DURATION; WEAKNESS;

EID: 77954919907     PISSN: 17512433     EISSN: None     Source Type: Journal    
DOI: 10.1586/ecp.10.28     Document Type: Review

References (192)

1. Emmons C, Hunsicker LG. Muromonab- CD3 (orthoclone OKT3): the first monoclonal antibody approved for therapeutic use. Iowa Med. 77(2), 78-82 (1987).
2. Ehrlich. Partial cell functions. Partial cell functions (1908).
3. Van Behring E, Kitasato S. Uber das zustandekommen der diphterie immunitat und der tetanus-immunitat bei thieren. Dt. Med. Wschr. 16, 1113-1114 (1890).
4. Milstein C, Cuello AC. Hybrid hybridomas and their use in immunohistochemistry. Nature 305(5934), 537-540 (1983).
5. Nadler LM, Stashenko P, Hardy R et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. Cancer Res. 40(9), 3147-3154 (1980).
6. Morrison Sl, Johnson MJ, Herzenberg LA, Oi VT. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl Acad. Sci. USA 81(21), 6851-6855 (1984).
7. Jones PT, Dear PH, Foote J, Neuberger MS, Winter G. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321(6069), 522-525 (1986).
8. Chames P, Van Regenmortel M, Weiss E, Baty D. Therapeutic antibodies: successes, limitations and hopes for the future. Br. J. Pharmacol. 157(2), 220-233 (2009).
9. Mccafferty J, Griffiths AD, Winter G, Chiswell DJ. Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348(6301), 552-554 (1990).
10. Lonberg N, Taylor LD, Harding FA et al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368(6474), 856-859 (1994).
11. Green Ll, Hardy MC, Maynard-Currie CE et al. Antigen-specific human monoclonal antibodies from mice engineered with human ig heavy and light chain yacs. Nat. Genet. 7(1), 13-21 (1994).
12. Reff ME, Hariharan K, Braslawsky G. Future of monoclonal antibodies in the treatment of hematologic malignancies. Cancer Control 9(2), 152-166 (2002).
13. Presta LG. Molecular engineering and design of therapeutic antibodies. Cur. Opin. Immunol. 20(4), 460-470 (2008).
14. Reinhart K, Karzai W. Anti-tumor necrosis factor therapy in sepsis: update on clinical trials and lessons learned. Crit. Care Med. 29(Suppl. 7), S121-S125 (2001).
15. Giamarellos-Bourboulis EJ. Immunomodulatory therapies for sepsis: unexpected effects with macrolides. Int. J. Antimicrob. Agents 32(Suppl. 1), S39-S43 (2008).
16. Finch RG. Design of clinical trials in sepsis: problems and pitfalls. J. Antimicrob. Chemother. 41(Suppl. A), 95-102 (1998).
17. Hofmann M, Stoss O, Gaiser T et al. Central Her2 IHC and fish analysis in a trastuzumab (Herceptin) Phase II monotherapy study: assessment of test sensitivity and impact of chromosome 17 polysomy. J. Clin. Pathol. 61(1), 89-94 (2008).
18. Furie RA, Petri MA, Wallace DJ et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 61(9), 1143-1151 (2009).
19. Presta LG. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv. Drug Deliv. Rev. 58(5-6), 640-656 (2006).
20. Jones TD, Crompton LJ, Carr FJ, Baker MP. Deimmunization of monoclonal antibodies. Methods Mol. Biol. 525, 405-423 (2009).
21. Loo L, Robinson MK, Adams GP. Antibody engineering principles and applications. Cancer J. 14(3), 149-153 (2008).
22. Filpula D. Antibody engineering and modification technologies. Biomol. Eng. 24(2), 201-215 (2007).
23. Jermutus L, Honegger A, Schwesinger F, Hanes J, Pluckthun A. Tailoring in vitro evolution for protein affinity or stability. Proc. Natl Acad. Sci. USA 98(1), 75-80 (2001).
24. Honegger A. Engineering antibodies for stability and efficient folding. Handb. Exp. Pharmacol. 181, 47-68 (2008).
25. Honegger A, Malebranche AD, Rothlisberger D, Pluckthun A. The influence of the framework core residues on the biophysical properties of immunoglobulin heavy chain variable domains. Protein Eng. Des. Sel. 2(3), 121-134 (2009).
26. Salfeld J. Isotype selection in antibody engineering. Nat. Biotechnol. 25(12), 1369-1372 (2007).
27. Desjarlais JR, Lazar GA, Zhukovsky EA, Chu SY. Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective. Drug Discov. Today 12(21-22), 898-910 (2007).
28. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 3(11), 2645-2668 (2004).
29. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7(9), 715-725 (2007).
30. Fishburn CS. The pharmacology of pegylation: balancing PD with PK to generate novel therapeutics. J. Pharm. Sci. 97(10), 4167-4183 (2008).
31. Beckman RA, Weiner LM, Davis HM. Antibody constructs in cancer therapy: protein engineering strategies to improve exposure in solid tumors. Cancer 109(2), 170-179 (2007).
32. Senter PD. Potent antibody drug conjugates for cancer therapy. Curr. Opin. Chem. Biol. 13(3), 235-244 (2009).
33. Singh Y, Palombo M, Sinko PJ. Recent trends in targeted anticancer prodrug and conjugate design. Curr. Med. Chem. 15(18), 1802-1826 (2008).
34. Thiel MA, Coster DJ, Standfield SD et al. Penetration of engineered antibody fragments into the eye. Clin. Exp. Immunol. 128(1), 67-74 (2002).
35. Holliger P, Hudson PJ. Engineered antibody fragments and the rise of single domains. Nat. Biotechnol. 23(9), 1126-1136 (2005).
36. Furrer E, Hulmann V, Urech DM. Intranasal delivery of ESBA105, a TNF-a-inhibitory scFv antibody fragment to the brain. J. Neuroimmunol. 215(1-2), 65-72 (2009).
37. Adams GP, Schier R, Mccall AM. High affinity restricts the localization and tumor penetration of single-chain Fv antibody molecules. Cancer Res. 61(12), 4750-4755 (2001).
38. Skerra A. Alternative non-antibody scaffolds for molecular recognition. Curr. Opin. Biotechnol. 18(4), 295-304 (2007).
39. Steinmeyer DE, Mccormick EL. The art of antibody process development. Drug Discov. Today 13(13-14), 613-618 (2008).
40. Lo AS, Zhu Q, Maeasco WA. Intracellular antibodies (intrabodies) and their therapeutic potential. Handb. Exp. Pharmacol. 181, 343-373 (2008).
41. Rocha-Lima CM, Soares HP, Raez LE, Singal R. EGFR targeting of solid tumors. Cancer Control 14(3), 295-304 (2007).
42. Chames P, Baty D. Bispecific antibodies for cancer therapy. Curr. Opin. Drug Discov. Devel. 12(2), 276-283 (2009).
43. Chouaib S. Tumor escape from the immune response: a major hurdle for successful immunotherapy of cancer? Tunis. Med. 83(Suppl. 12), 7-10 (2005).
44. Staerz UD, Kanagawa O, Bevan MJ. Hybrid antibodies can target sites for attack by T cells. Nature 314(6012), 628-631 (1985).
45. Uherek C, Tonn T, Uherek B et al. Retargeting of natural killer-cell cytolytic activity to erbb2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood 100(4), 1265-1273 (2002).
46. Chapoval AI, Nelson H, Thibault C, Penna C, Dean P. Bifunctional antibody retargeting in vivo-activated T lymphocytes: simplifying clinical application. J. Hematother. 4(6), 571-577 (1995).
47. Segal DM, Qian JH, Garrido MA et al. Targeting of cytotoxic cells against tumors with heterocrosslinked, bispecific antibodies. Princess Takamatsu. Symp. 19, 323-331 (1988).
48. Taylor RP, Sutherland WM, Martin EN et al. Bispecific monoclonal antibody complexes bound to primate erythrocyte complement receptor 1 facilitate virus clearance in a monkey model. J. Immunol. 158(2), 842-850 (1997).
49. Pardridge WM. Re-engineering biopharmaceuticals for delivery to brain with molecular trojan horses. Bioconjug. Chem. 19(7), 1327-1338 (2008).
50. Goldenberg DM, Rossi EA, Sharkey RM, Mcbride WJ, Chang CH. Multifunctional antibodies by the dock-and-lock method for improved cancer imaging and therapy by pretargeting. J. Nucl. Med. 49(1), 158-163 (2008).
51. Ford CH, Osborne PA, Rego BG, Mathew A. Bispecific antibody targeting of doxorubicin to carcinoembryonic antigen-expressing colon cancer cell lines in vitro and in vivo. Int. J. Cancer 92(6), 851-855 (2001).
52. Goldenberg DM, Sharkey RM, Paganelli G, Barbet J, Chatal JF. Antibody pretargeting advances cancer radioimmunodetection and radioimmunotherapy. J. Clin. Oncol. 24(5), 823-834 (2006).
53. Bode C, Runge MS, Branscomb EE, Newell JB, Matsueda GR, Haber E. Antibody-directed fibrinolysis. An antibody specific for both fibrin and tissue plasminogen activator. J. Biol. Chem. 264(2), 944-948 (1989).
54. Boado RJ, Lu JZ, Hui EK, Pardridge WM. IgG-single chain Fv fusion protein therapeutic for Alzheimer's disease: expression in CHO cells and pharmacokinetics and brain delivery in the rhesus monkey. Biotechnol. Bioeng. 100(4), 1251-1258 (2009).
55. Vallera DA, Todhunter DA, Kuroki DW, Shu Y, Sicheneder A, Chen H. A bispecific recombinant immunotoxin, DT2219, targeting human CD19 and CD22 receptors in a mouse xenograft model of B-cell leukemia/lymphoma. Clin. Cancer Res. 11(10), 3879-3888 (2005).
56. Vallera DA, Chen H, Sicheneder AR, Panoskaltsis-Mortari A, Taras EP. Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy. Leuk. Res. 33(9), 1233-1242 (2009).
57. Robinson MK, Hodge KM, Horak E et al. Targeting erbB2 and erbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro. Br. J. Cancer 99(9), 1415-1425 (2008).
58. Wu C, Ying H, Bose S et al. Molecular construction and optimization of anti-human IL-1a/p dual variable domain immunoglobulin (DVD-Ig™) molecules. mAbs 1(4), 339-347 (2009).
59. Feldmann G, Dhara S, Fendrich V et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 67(5), 2187-2196 (2007).
60. Gabrilovich DI. Combination of chemotherapy and immunotherapy for cancer: a paradigm revisited. Lancet Oncol. 8(1), 2-3 (2007).
61. Stinchcombe TE, Fried D, Morris DE, Socinski MA. Combined modality therapy for stage III non-small cell lung cancer. Oncologist 11(7), 809-823 (2006).
62. Liu Z, Stoll VS, Devries PJ et al. A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood 110(7), 2408-2413 (2007).
63. Madrenas J, Chau LA, Teft WA et al. Conversion of CTLA-4 from inhibitor to activator of T cells with a bispecific tandem single-chain Fv ligand. J. Immunol. 172(10), 5948-5956 (2004).
64. Lu D, Kotanides H, Jimenez X et al. Acquired antagonistic activity of a bispecific diabody directed against two different epitopes on vascular endothelial growth factor receptor 2. J. Immunol. Methods 230(1-2), 159-171 (1999).
65. Michaelson JS, Demarest SJ, Miller B et al. Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting TRAIL-R2 and LTpR. MAbs 1(2), 128-141 (2009).
66. Nisonoff A, Rivers MM. Recombination of a mixture of univalent antibody fragments of different specificity. Arch. Biochem. Biophys. 93, 460-462 (1961).
67. Weiner LM, Clark JI, Ring DB, Alpaugh RK. Clinical development of 2B1, a bispecific murine monoclonal antibody targeting c-erbB-2 and Fc g RIII. J. Hematother. 4(5), 453-456 (1995).
68. Weiner LM, Clark JI, Davey M et al. Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc g RIII. Cancer Res. 55(20), 4586-4593 (1995).
69. Borghaei H, Alpaugh RK, Bernardo P et al. Induction of adaptive anti-Her2/Neu immune responses in a Phase 1B/2 trial of 2B1 bispecific murine monoclonal antibody in metastatic breast cancer (E3194): a trial coordinated by the Eastern Cooperative Oncology Group. J. Immunother. 30(4), 455-467 (2007).
70. Renner C, Hartmann F, Pfreundschuh M. Treatment of refractory Hodgkin's disease with an anti-CD16/CD30 bispecific antibody. Cancer Immunol. Immunother. 45(3-4), 184-186 (1997). (Pubitemid 27521455)
71. Hartmann F, Renner C, Jung W et al. Anti-CD16/CD30 bispecific antibody treatment for hodgkin's disease: role of infusion schedule and costimulation with cytokines. Clin. Cancer Res. 7(7), 1873-1881 (2001).
72. Lindhofer H, Mocikat R, Steipe B, Thierfelder S. Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies. J. Immunol. 155(1), 219-225 (1995).
73. Zeidler R, Mysliwietz J, Csanady M et al. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Br. J. Cancer 83(2), 261-266 (2000).
74. Morecki S, Lindhofer H, Yacovlev E, Gelfand Y, Ruf P, Slavin S. Induction of long-lasting antitumor immunity by concomitant cell therapy with allogeneic lymphocytes and trifunctional bispecific antibody. Exp. Hematol. 36(8), 997-1003 (2008).
75. Sebastian M, Passlick B, Friccius-Quecke H et al. Treatment of non-small cell lung cancer patients with the trifunctional monoclonal antibody catumaxomab (anti-EpCAM x anti-CD3): a Phase I study. Cancer Immunol. Immunother. 56(10), 1637-1644 (2007).
76. Burges A, Wimberger P, Kumper C et al. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM x anti-CD3 antibody: a Phase I/II study. Clin. Cancer Res. 13(13), 3899-3905 (2007).
77. Kiewe P, Thiel E. Ertumaxomab: a trifunctional antibody for breast cancer treatment. Expert Opin. Investig. Drugs 17(10), 1553-1558 (2008).
78. Stanglmaier M, Faltin M, Ruf P, Bodenhausen A, Schroder P, Lindhofer H. Bi20 (fBTA05), a novel trifunctional bispecific antibody (anti-CD20 x anti-CD3), mediates efficient killing of b-cell lymphoma cells even with very low CD20 expression levels. Int. J. Cancer 123(5), 1181-1189 (2008).
79. Molecule of the month: catumaxomab. Drug News Perspect. 22(5), 283 (2009).
80. Parsons S, Murawa PX, Koralewski P et al. Intraperitoneal treatment of malignant ascites due to epithelial tumors with catumaxomab: a Phase II/III study. J. Clin. Oncol. 26(Suppl.), 3000 (2008).
81. Kiewe P, Hasmuller S, Kahlert S et al. Phase I trial of the trifunctional anti-Her2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin. Cancer Res. 12(10), 3085-3091 (2006).
82. Graziano RF, Guptill P. Chemical production of bispecific antibodies. Methods Mol. Biol. 283, 71-85 (2004).
83. Nolan O, O'Kennedy R. Chemical production of bifunctional antibodies. Biochem. Soc. Trans. 20(1), S60 (1992).
84. Valone FH, Kaufman PA, Guyre PM et al. Clinical trials of bispecific antibody MDX-210 in women with advanced breast or ovarian cancer that overexpresses Her-2/Neu. J. Hematother. 4(5), 471-475 (1995).
85. Curnow RT. Clinical experience with CD64-directed immunotherapy. An overview. Cancer Immunol. Immunother. 45(3-4), 210-215 (1997).
86. Repp R, Van Ojik HH, Valerius T et al. Phase I clinical trial of the bispecific antibody MDX-h210 (anti-Fc g RI x anti-Her-2/Neu) in combination with filgrastim (G-CSF) for treatment of advanced breast cancer. Br. J. Cancer 89(12), 2234-2243 (2003).
87. Gall JM, Davol PA, Grabert RC, Deaver M, Lum LG. T cells armed with anti-CD3 x anti-CD20 bispecific antibody enhance killing of CD20 + malignant B cells and bypass complement-mediated rituximab resistance in vitro. Exp. Hematol. 33(4), 452-459 (2005).
88. Sen M, Wankowski DM, Garlie NK et al. Use of anti-CD3 x anti-Her2/Neu bispecific antibody for redirecting cytotoxicity of activated T cells toward Her2/Neu+ tumors. J. Hematother. Stem Cell Res. 10(2), 247-260 (2001).
89. Nolan O, O'Kennedy R. Bifunctional antibodies: concept, production and applications. Biochim. Biophys. Acta 1040(1), 1-11 (1990).
90. Segal DM, Weiner GJ, Weiner LM. Bispecific antibodies in cancer therapy. Curr. Opin. Immunol. 11(5), 558-562 (1999).
91. Van Spriel AB, Van Ojik HH, Van De Winkel JG. Immunotherapeutic perspective for bispecific antibodies. Immunol. Today 21(8), 391-397 (2000).
92. Gebauer M, Skerra A. Engineered protein scaffolds as next-generation antibody therapeutics. Curr. Opin. Chem. Biol 13(3), 245-255 (2009).
93. Stumpp MT, Binz HK, Amstutz P. Darpins: a new generation of protein therapeutics. Drug Discov. Today 13(15-16), 695-701 (2008).
94. Ridgway JB, Presta LG, Carter P. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 9(7), 617-621 (1996).
95. Zhu Z , Presta LG, Zapata G, Carter P. Remodeling domain interfaces to enhance heterodimer formation. Protein Sci. 6(4), 781-788 (1997).
96. Merchant AM, Zhu Z, Yuan JG et al. An efficient route to human bispecific IgG. Nat. Biotechnol. 16(7), 677-681 (1998).
97. Davis JH, Aperlo C, Li Y et al. Seedbodies: fusion proteins based on strand-exchange engineered domain (seed) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies. Protein Eng. Des. Sel. 23(4), 195-202
98. Muller KM, Arndt KM, Strittmatter W, Pluckthun A. The first constant domain CH1 and CL of an antibody used as heterodimerization domain for bispecific miniantibodies. FEBS Lett. 422(2), 259-264 (1998).
99. De Kruif J, Logtenberg T. Leucine zipper dimerized bivalent and bispecific scFv antibodies from a semi-synthetic antibody phage display library. J. Biol. Chem. 271(13), 7630-7634 (1996).
100. Kostelny SA, Cole MS, Tso JY. Formation of a bispecific antibody by the use of leucine zippers. J. Immunol. 148(5), 1547-1553 (1992).
101. Muller KM, Arndt KM, Pluckthun A. A dimeric bispecific miniantibody combines two specificities with avidity. FEBS Lett. 432(1-2), 45-49 (1998).
102. Holliger P, Prospero T, Winter G. 'Diabodies': small bivalent and bispecific antibody fragments. Proc. Natl Acad. Sci. USA 90(14), 6444-6448 (1993).
103. Lu D, Jimenez X, Zhang H et al. Di-diabody: a novel tetravalent bispecific antibody molecule by design. J. Immunol. Methods 279(1-2), 219-232 (2003).
104. Kipriyanov SM, Moldenhauer G, Schuhmacher J et al. Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J. Mol. Biol. 293(1), 41-56 (1999).
105. Schmiedl A, Breitling F, Dubel S. Expression of a bispecific dsFv-dsFv' antibody fragment in Escherichia coli. Protein Eng. 13(10), 725-734 (2000).
106. Kipriyanov SM. Generation of bispecific and tandem diabodies. Methods Mol. Biol. 562, 177-193 (2009).
107. Kriangkum J, Xu B, Nagata LP, Fulton RE, Suresh MR. Bispecific and bifunctional single chain recombinant antibodies. Biomol. Eng. 18(2), 31-40 (2001).
108. Volkel T, Korn T, Bach M, Muller R, Kontermann RE. Optimized linker sequences for the expression of monomeric and dimeric bispecific single-chain diabodies. Protein Eng. 14(10), 815-823 (2001).
109. Kontermann RE, Volkel T, Korn T. Production of recombinant bispecific antibodies. Methods Mol. Biol. 248, 227-242 (2004).
110. Demarest SJ, Chen G, Kimmel BE et al. Engineering stability into Escherichia coli secreted Fabs leads to increased functional expression. Protein Eng. Des. Sel. 19(7), 325-336 (2006).
111. Demarest SJ, Glaser SM. Antibody therapeutics, antibody engineering, and the merits of protein stability. Curr. Opin. Drug Discov. Devel. 11(5), 675-687 (2008).
112. Demarest SJ, Rogers J, Hansen G. Optimization of the antibody CH3 domain by residue frequency analysis of IgG sequences. J. Mol. Biol. 335(1), 41-48 (2004).
113. Ewert S, Honegger A, Pluckthun A. Stability improvement of antibodies for extracellular and intracellular applications: CDR grafting to stable frameworks and structure-based framework engineering. Methods 34(2), 184-199 (2004).
114. Jager M, Pluckthun A. Domain interactions in antibody Fv and scFv fragments: effects on unfolding kinetics and equilibria. FEBS Lett. 462(3), 307-312 (1999).
115. Worn A, Pluckthun A. Stability engineering of antibody single-chain Fv fragments. J. Mol. Biol. 305(5), 989-1010 (2001).
116. Worn A, Pluckthun A. Different equilibrium stability behavior of scFv fragments: identification, classification, and improvement by protein engineering. Biochemistry 38(27), 8739-8750 (1999).
117. Christ D, Famm K, Winter G. Repertoires of aggregation-resistant human antibody domains. Protein Eng. Des. Sel. 20(8), 413-416 (2007).
118. Chennamsetty N, Voynov V, Kayser V, Helk B, Trout BL. Design of therapeutic proteins with enhanced stability. Proc. Natl Acad. Sci. USA 106(29), 11937-11942 (2009).
119. Fernandez-Escamilla AM, Rousseau F, Schymkowitz J, Serrano L. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat. Biotechnol. 22(10), 1302-1306 (2004).
120. Linding R, Schymkowitz J, Rousseau F, Diella F, Serrano L. A comparative study of the relationship between protein structure and p-aggregation in globular and intrinsically disordered proteins. J. Mol. Biol. 342(1), 345-353 (2004).
121. Reumers J, Maurer-Stroh S, Schymkowitz J, Rousseau F. Protein sequences encode safeguards against aggregation. Hum. Mutat. 30(3), 431-437 (2009).
122. Kipriyanov SM, Moldenhauer G, Braunagel M et al. Effect of domain order on the activity of bacterially produced bispecific single-chain Fv antibodies. J. Mol. Biol. 330(1), 99-111 (2003).
123. Le Gall F, Reusch U, Little M, Kipriyanov SM. Effect of linker sequences between the antibody variable domains on the formation, stability and biological activity of a bispecific tandem diabody. Protein Eng. Des. Sel. 17(4), 357-366 (2004).
124. Jordan JL, Arndt JW, Hanf K et al. Structural understanding of stabilization patterns in engineered bispecific Ig-like antibody molecules. Proteins 77(4), 832-841 (2009).
125. Rothlisberger D, Honegger A, Pluckthun A. Domain interactions in the Fab fragment: a comparative evaluation of the single-chain Fv and Fab format engineered with variable domains of different stability. J. Mol. Biol. 347(4), 773-789 (2005).
126. Grosse-Hovest L, Hartlapp I, Marwan W, Brem G, Rammensee HG, Jung G. A recombinant bispecific single-chain antibody induces targeted, supra-agonistic cd28-stimulation and tumor cell killing. Eur. J. Immunol. 33(5), 1334-1340 (2003).
127. Dreier T, Baeuerle PA, Fichtner I et al. 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(8), 4397-4402 (2003).
128. Dreier T, Lorenczewski G, Brandl C et al. Extremely potent, rapid and costimulation- independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int. J. Cancer 100(6), 690-697 (2002).
129. Brischwein K, Schlereth B, Guller B et al. MT110 : a novel bispecific single-chain antibody construct with high efficacy in eradicating established tumors. Mol. Immunol. 43(8), 1129-1143 (2006).
130. Lutterbuese R, Raum T, Kischel R et al. Potent control of tumor growth by CEA/CD3-bispecific single-chain antibody constructs that are not competitively inhibited by soluble CEA. J. Immunother. 32(4), 341-352 (2009).
131. Baeuerle PA, Kufer P, Bargou R. Bite: teaching antibodies to engage T-cells for cancer therapy. Curr. Opin. Mol. Ther. 11(1), 22-30 (2009).
132. Brischwein K, Parr L, Pflanz S et al. Strictly target cell-dependent activation of T cells by bispecific single-chain antibody constructs of the BiTE class. J. Immunother. 30(8), 798-807 (2007).
133. Nagorsen D, Bargou R, Ruttinger D, Kufer P, Baeuerle PA, Zugmaier G. Immunotherapy of lymphoma and leukemia with T-cell engaging bite antibody blinatumomab. Leuk. Lymphoma 50(6), 886-891 (2009).
134. Bargou R, Leo E, Zugmaier G et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321(5891), 974-977 (2008).
135. Schlereth B, Quadt C, Dreier T et al. T-cell activation and b-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct. Cancer Immunol. Immunother. 55(5), 503-514 (2006).
136. Topp M, Goekbuget N, Kufer P et al., Blinatumomab (anti-CD19 BiTE® ) for targeted therapy of minimal residual disease (MRD) in patients with B-precursor acute lymphoblastic leukemia (ALL) update of an ongoing GMALL Phase II Study. Presented at: 14th Congress of theEHA. Berlin, Germany, 4 June 2009 (Abstract 2482).
137. Amann M, D'argouges S, Lorenczewski G et al. Antitumor activity of an EpCAM/CD3-bispecific bite antibody during long-term treatment of mice in the absence of T-cell anergy and sustained cytokine release. J. Immunother. 32(5), 452-464 (2009).
138. Haas C, Krinner E, Brischwein K et al. Mode of cytotoxic action of T cell- engaging BiTE antibody MT110. Immunobiology 214(6), 441-453 (2009).
139. Witthauer J, Schlereth B, Brischwein K et al. 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(3), 471-481 (2009).
140. Schlereth B, Fichtner I, Lorenczewski G et al. 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(7), 2882-2889 (2005).
141. Amann M, Brischwein K, Lutterbuese P et al. Therapeutic window of MuS110, a single-chain antibody construct bispecific for murine EpCAM and murine CD3. Cancer Res. 68(1), 143-151 (2008).
142. Jendreyko N, Popkov M, Beerli RR et al. Intradiabodies, bispecific, tetravalent antibodies for the simultaneous functional knockout of two cell surface receptors. J. Biol. Chem. 278(48), 47812-47819 (2003).
143. Lu D, Zhang H, Ludwig D et al. Simultaneous blockade of both the epidermal growth factor receptor and the insulin-like growth factor receptor signaling pathways in cancer cells with a fully human recombinant bispecific antibody. J. Biol. Chem. 279(4), 2856-2865 (2004).
144. Connelly RJ, Hayden MS, Scholler JK et al. Mitogenic properties of a bispecific single-chain Fv-Ig fusion generated from CD2-specific mAb to distinct epitopes. Int. Immunol. 10(12), 1863-1872 (1998).
145. Alt M, Muller R, Kontermann RE. Novel tetravalent and bispecific IgG-like antibody molecules combining single-chain diabodies with the immunoglobulin g1 Fc or CH3 region. FEBS Lett. 454(1-2), 90-94 (1999).
146. Lu D, Zhang H, Koo H et al. A fully human recombinant IgG-like bispecific antibody to both the epidermal growth factor receptor and the insulin-like growth factor receptor for enhanced antitumor activity. J. Biol. Chem. 280(20), 19665-19672 (2005).
147. Dimasi N, Gao C, Fleming R et al. The design and characterization of oligospecific antibodies for simultaneous targeting of multiple disease mediators. J. Mol. Biol. 393(3), 672-692 (2009).
148. Mabry R, Gilbertson DG, Frank A et al. A dual-targeting PDGFRp/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo. MAbs 2(1), 20-34 (2010).
149. Reiter Y, Brinkmann U, Lee B, Pastan I. Engineering antibody Fv fragments for cancer detection and therapy: disulfide- stabilized Fv fragments. Nat. Biotechnol. 14(10), 1239-1245 (1996).
150. Reiter Y, Pastan I. Recombinant Fv immunotoxins and Fv fragments as novel agents for cancer therapy and diagnosis. Trends Biotechnol. 16(12), 513-520 (1998).
151. Muyldermans S, Baral TN, Retamozzo VC et al. Camelid immunoglobulins and nanobody technology. Vet. Immunol. Immunopathol. 128(1-3), 178-183 (2009).
152. Holt LJ, Herring C, Jespers LS, Woolven BP, Tomlinson IM. Domain antibodies: proteins for therapy. Trends Biotechnol. 21(11), 484-490 (2003).
153. Ryckaert S, Pardon E, Steyaert J, Callewaert N. Isolation of antigen- binding camelid heavy chain antibody fragments (nanobodies) from an immune library displayed on the surface of pichia pastoris. J. Biotechnol. 145(2), 93-98 (2009).
154. Vandenbroucke K, De Haard H, Beirnaert E et al. Orally administered L. lactis secreting an anti-TNF nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol. 3, 49-56 (2010).
155. Shen J, Vil MD, Jimenez X, Iacolina M, Zhang H, Zhu Z. Single variable domain- IgG fusion. A novel recombinant approach to fc domain-containing bispecific antibodies. J. Biol. Chem. 281(16), 10706-10714 (2006).
156. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol. Ther. 117(2), 244-279 (2008).
157. Ratner M. IL-1 trap go-ahead. Nat. Biotechnol. 26(5), 485 (2008).
158. Shear NH, Prinz J, Papp K, Langley RG, Gulliver WP. Targeting the interleukin-12/23 cytokine family in the treatment of psoriatic disease. J. Cutan. Med. Surg. 12(Suppl. 1), S1-S10 (2008).
159. Garcia-Rodriguez C, Levy R, Arndt JW et al. Molecular evolution of antibody cross-reactivity for two subtypes of type a botulinum neurotoxin. Nat. Biotechnol. 25(1), 107-116 (2007).
160. Bostrom J, Yu SF, Kan D et al. Variants of the antibody herceptin that interact with Her2 and VEGF at the antigen binding site. Science 323(5921), 1610-1614 (2009).
161. Wu C, Ying H, Grinnell C et al. Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat. Biotechnol. 25(11), 1290-1297 (2007).
162. Bagshawe KD. Antibody-directed enzyme prodrug therapy (ADEPT) for cancer. Expert Rev. Anticancer Ther. 6(10), 1421-1431 (2006).
163. Kuo SR, Alfano RW, Frankel AE, Liu JS. Antibody internalization after cell surface antigen binding is critical for immunotoxin development. Bioconjug. Chem. DOI: 10.1021/bc900333j (2009) (Epub ahead of print).
164. Chen SY, Bagley J, Marasco WA. Intracellular antibodies as a new class of therapeutic molecules for gene therapy. Hum. Gene Ther. 5(5), 595-601 (1994). (Pubitemid 24310550)
165. Mhashilkar AM, Bagley J, Chen SY, Szilvay AM, Helland DG, Marasco WA. Inhibition of HIV-1 Tat-mediated LTR transactivation and HIV-1 infection by anti-tat single chain intrabodies. EMBO J. 14(7), 1542-1551 (1995).
166. Wheeler YY, Kute TE, Willingham MC, Chen SY, Sane DC. Intrabody-based strategies for inhibition of vascular endothelial growth factor receptor-2: effects on apoptosis, cell growth, and angiogenesis. FASEB J. 17(12), 1733-1735 (2003).
167. Cohen PA, Mani JC, Lane DP. Characterization of a new intrabody directed against the N-terminal region of human p53. Oncogene 17(19), 2445-2456 (1998).
168. Auf Der Maur A, Escher D, Barberis A. Antigen-independent selection of stable intracellular single-chain antibodies. FEBS Lett. 508(3), 407-412 (2001).
169. Shaki-Loewenstein S, Zfania R, Hyland S, Wels WS, Benhar I. A universal strategy for stable intracellular antibodies. J. Immunol. Methods 303(1-2), 19-39 (2005).
170. Fisher RI. Treating Hodgkin's disease with bispecific antibodies: both patients and antibody are limiting. Clin. Cancer Res. 7(7), 1835-1836 (2001).
171. Posey JA, Raspet R, Verma U et al. A pilot trial of GM-CSF and MDX-h210 in patients with erbB-2-positive advanced malignancies. J. Immunother. 22(4), 371-379 (1999).
172. Repp R, Valerius T, Wieland G et al. G-CSF-stimulated PMN in immunotherapy of breast cancer with a bispecific antibody to Fc g RI and to Her-2/Neu (MDX-210). J. Hematother. 4(5), 415-421 (1995).
173. Valone FH, Kaufman PA, Guyre PM et al. Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene Her-2/Neu. J. Clin. Oncol. 13(9), 2281-2292 (1995).
174. Fury MG, Lipton A, Smith KM, Winston CB, Pfister DG. A Phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors. Cancer Immunol. Immunother. 57(2), 155-163 (2008).
175. Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol. 4(7), 397-406 (2003).
176. D'argouges S, Wissing S, Brandl C et al. Combination of rituximab with blinatumomab (MT103/MEDI-538), a T cell-engaging CD19-/CD3-bispecific antibody, for highly efficient lysis of human B lymphoma cells. Leuk. Res. 33(3), 465-473 (2009).
177. Amgen Inc. WO/2009/089004 (2009).
178. Abbott Laboratories. WO/2008/082651 A2 (2008).
179. Abbott Laboratories. US 7491516 (2009).
180. TRION Pharma www.trionpharma.de
181. Catumaxomab ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term= Catumaxomab
182. Ertumaxomab ClinicalTrials.gov. www.clinicaltrials.gov/ct2/results?term= ertumaxomab
183. ClinicalTrials.gov. CD20Bi or Her2Bi search www.clinicaltrials.gov/ct2/ results?term=CD20Bi+OR+Her2Bi
184. ClinicalTrials.gov. CD20Bi search www.clinicaltrials.gov/ct2/results? term=CD20Bi
185. Local treatment of metastatic melanoma with autologous lymphocytes and the bispecific antibody rM28 www.clinicaltrials.gov/ct2/show/NCT00204594?term= rm28&rank=1
186. Phase I study of MT110 in lung cancer (adenocarcinoma and small cell), gastric cancer or adenocarcinoma of the gastro- esophageal junction (GI), colorectal cancer (CRC), breast cancer, hormone-refractory prostate cancer, and ovarian cancer (MT110-101) www.clinicaltrials.gov/ct2/show/NCT00635596?term=MT- 110&rank=1
187. DT2219ARL immunotoxin in treating patients with B-cell leukemia or lymphoma that has relapsed or not responded to treatment. www.clinicaltrials. gov/ct2/show/NCT00889408?term=DT2219&rank=1
188. The Wall Street Journal. Pfizer halts enrollment in cancer-drug trial http://online.wsj.com/article/SB10001424 052748703790404574467140548602208.html
189. Merrimack. Pipeline: MM-111 www.merrimackpharma.com/pipeline/mm111.html
190. mAb2: An antibody with inbuilt additiona functions, www. f-star. com /technology-m ab.htm l
191. Citeline TrialTrove www.citeline.com/trialtrove.html
192. Antibody therapy in treating patients with refractory or relapsed non-Hodgkin's lymphoma or chronic lymphocytic leukemia www.clinicaltrials.gov/ ct2/show/NCT00014560?term=bsab+4g7xh22&rank=1