The Future of Antibody Therapy

Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/4)


Antibodies have been used successfully as therapeutics for over 100 years. The successful development of therapeutic human(ized) monoclonal antibodies (mAbs) in the last 20 years has demonstrated the potency of mAbs but also revealed some of their limitations. Studies in animals and humans demonstrated that it is possible to overcome some of these limitations using mixtures of mAbs or polyclonal antibody (pAb) preparations. pAbs from human and animal plasma are efficacious and safe therapeutics for the treatment of many diseases. Novel technologies are being developed for the production of human pAbs in genetically engineered animals. Immunization of such animals should allow the production of effective and safe high-titer antibody preparations for the treatment of infectious diseases, cancer, and autoimmunity.


Gene Conversion Snake Venom Antibody Therapy Antibody Preparation Human Artificial Chromosome 


  1. Adams GP, Weiner LM (2005) Monoclonal antibody therapy of cancer. Nat Biotechnol 23:1147–1157CrossRefPubMedGoogle Scholar
  2. Andresen I, Kovarik JM, Spycher M, Bolli R (2000) Product equivalence study comparing the tolerance, pharmacokinetics and pharmacodynamics of various human immunoglobulin-G formulations. J Clin Pharmacol 40:722–730CrossRefPubMedGoogle Scholar
  3. Badger C, Anasetti C, Davis J, Bernstein I (1987) Treatment of malignancy with unmodified antibody. Pathol Immunopathol Res 6:419–434CrossRefPubMedGoogle Scholar
  4. Beiras-Fernandez A, Chappell D, Hammer C, Thein E (2006) Influence of polyclonal anti-thymocyte globulins upon ischemia-reperfusion injury in a non-human primate model. Transpl Immunol 15:273–279CrossRefPubMedGoogle Scholar
  5. Bonnefoy-Berard N, Revillard JP (1996) Mechanisms of immunosuppression induced by antithymocyte globulins and OKT3. J Heart Lung Transplant 15:435–442PubMedGoogle Scholar
  6. Bonnefoy-Berard N, Genestier L, Flacher M, Rouault JP, Lizard G, Mutin M, Revillard JP (1994) Apoptosis induced by polyclonal antilymphocyte globulins in human B-cell lines. Blood 83:1051–1059PubMedGoogle Scholar
  7. Brennan DC, Daller JA, Lake KD, Cibrik D, Del Castillo D, et al (2006) Rabbit anti-thymocyte globulin compared to basiliximab for induction in renal transplantation. New England J Med 355:1967–1977CrossRefGoogle Scholar
  8. Buchwald UK, Pirofski L (2003) Immune therapy for infectious diseases at the dawn of the 21st century: the past, present and future role of antibody therapy, therapeutic vaccination and biological response modifiers. Curr Pharm Des 9:945–968CrossRefPubMedGoogle Scholar
  9. Burton CM, Andersen CB, Jensen AS, Iversen M, Milman N, Boesgaard S, Arendrup H, Eliasen K, Carlsen J (2006) The incidence of acute cellular rejection after lung transplantation: a comparative study of anti-thymocyte globulin and daclizumab. J Heart Lung Transplant 25:638–647CrossRefPubMedGoogle Scholar
  10. Byrd JC, Waselenko JK, Maneatis TJ, Murphy T, Ward FT, Monahan BP, Sipe MA, Donegan S, White CA (1999) Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance. J Clin Oncol 17:791–795PubMedGoogle Scholar
  11. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754–758CrossRefPubMedGoogle Scholar
  12. Casadevall A (2002) Passive antibody administration (immediate immunity) as a specific defense against biological weapons. Emerg Infect Dis 8:833–841PubMedGoogle Scholar
  13. Casadevall A, Scharff MD (1994) Serum therapy revisited: animal models of infection and development of passive antibody therapy. Antimicrob Agents Chemother 38:1695–1702PubMedGoogle Scholar
  14. Casadevall A, Scharff MD (1995) Return to the past: the case for antibody-based therapies in infectious diseases. Clin Infect Dis 21:150–161PubMedGoogle Scholar
  15. Casadevall A, Dadachova E, Pirofski LA (2004) Passive antibody therapy for infectious diseases. Nat Rev Microbiol 2:695–703CrossRefPubMedGoogle Scholar
  16. Chow KU, Sommerlad WD, Boehrer S, Schneider B, Seipelt G, Rummel MG, Hoelzer D, Mitrou PS, Weidmann E (2002) Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro; the role of cytokines, complement and caspases. Haematologica 87:33–43PubMedGoogle Scholar
  17. Church AC (2003) Clinical advances in therapies targeting the interleukin-2 receptor. QJM 96:91–102CrossRefPubMedGoogle Scholar
  18. Czuczman MS (1999) CHOP plus rituximab chemoimmunotherapy of indolent B-cell lymphoma. Semin Oncol 26:88–96PubMedGoogle Scholar
  19. Czuczman MS, Grillo-Lopez AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C (1999) Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268–276PubMedGoogle Scholar
  20. Debets R, Savelkoul HF (1994) Cytokine antagonists and their potential therapeutic use. Immunol Today 15:455CrossRefPubMedGoogle Scholar
  21. Dubin G (2002) Extracellular proteases of Staphylococcus spp. Biol Chem 383:1075–1086CrossRefPubMedGoogle Scholar
  22. Finckh A, Simard JF, Duryea J, Liang MH, Huang J, Daneel S, Forster A, Gabay C, Guerne PA (2006) The effectiveness of anti-tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis: a population-based study. Arthritis Rheum 54:54–59CrossRefPubMedGoogle Scholar
  23. Finkelman FD, Madden KB, Morris SC, Holmes JM, Boiani N, Katona IM, Maliszewski CR (1993) Anti-cytokine antibodies as carrier proteins: prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes. J Immunol 151:1235–1244PubMedGoogle Scholar
  24. Fojo AT, Menefee M (2005) Microtubule targeting agents: basic mechanism of multidrug resistance (MDR). Semin Oncol 32:S3–8CrossRefPubMedGoogle Scholar
  25. Foster TJ, Hook M (1998) Surface protein adhesins of Staphylococcus aureus. Trends Microbiol 6:484–488CrossRefPubMedGoogle Scholar
  26. Fowler VG Jr, Fey PD, Reller LB, Chamis AL, Corey GR, Rupp ME (2001) The intercellular adhesin locus ica is present in clinical isolates of Staphylococcus aureus from bacteremic patients with infected and uninfected prosthetic joints. Med Microbiol Immunol (Berl) 189:127–131CrossRefGoogle Scholar
  27. Ghetie V, Ward ES (2000) Multiple roles for the major histocompatibility complex class I-related Fc receptor RcRn. Annu Rev Immunol 18:739–766CrossRefPubMedGoogle Scholar
  28. Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna M (2001) CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood 98:3383–3389CrossRefPubMedGoogle Scholar
  29. Gomez MI, Lee A, Reddy B, Muir A, Soong G, Pitt A, Cheung A, Prince A (2004) Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nat Med 20:842–848CrossRefGoogle Scholar
  30. Gotz F, Verheij HM, Rosenstein R (1998) Staphylococcal lipases: molecular characterization, secretion, and processing. Chem Phys Lipids 93:15–25CrossRefPubMedGoogle Scholar
  31. Herbst R, Langer C (2002) Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers. Semin Oncol 29:27–36CrossRefPubMedGoogle Scholar
  32. Heremans H, Dillen C, Put W, Damme JV, Billiau A (1992) Protective effect of anti-interleukin (IL)-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels. Eur J Immunol 22:2395–2401CrossRefPubMedGoogle Scholar
  33. Herrera L, Yarbrough S, Ghetie V, Aquino DB, Vitetta ES (2003) Treatment of SCID/human B cell precursor ALL with anti-CD19 and anti-CD22 immunotoxins. Leukemia 17:334–338CrossRefPubMedGoogle Scholar
  34. Hillmen P (2004) Advancing therapy for chronic lymphocytic leukemia—the role of rituximab. Semin Oncol 31:22–26CrossRefPubMedGoogle Scholar
  35. Hiramatsu K (2001) Vancomycin-resistant Staphylococcus aureus: a new model of antibiotic resistance. Lancet Infect Dis 1:147–155CrossRefPubMedGoogle Scholar
  36. Holliger P, Hudson PJ (2005) Engineered antibody fragments and the rise of the single domains. Nat Biotechnol 23:1126–1136CrossRefPubMedGoogle Scholar
  37. Hoogenboom HR (2005) Selecting and screening recombinant antibody libraries. Nat Biotechnol 23:1105–1116CrossRefPubMedGoogle Scholar
  38. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefPubMedGoogle Scholar
  39. Hwang WY, Foote J (2005) Immunogenicity of engineered antibodies. Methods 36:3–10CrossRefPubMedGoogle Scholar
  40. Khazaeli MB, Conry RM, LoBuglio AF (1994) Human immune response to monoclonal antibodies. J Immunother 15:42–52CrossRefGoogle Scholar
  41. Klein B, Brailly H (1995) Cytokine-binding proteins: stimulating antagonists. Immunol Today 16:216CrossRefPubMedGoogle Scholar
  42. Knight KL, Crane MA (1994) Generating the antibody repertoire in rabbit. Adv Immunol 56:179–218CrossRefPubMedGoogle Scholar
  43. Knight RJ, Kerman RH, Zela S, Pdbielski J, Podder H, Van Buren CT, Katz S, Kahan BD (2006) Pancreas transplantation utilizing thymoglobulin, sirolimus and cyclosporine. Transplantation 81:1101–1105CrossRefPubMedGoogle Scholar
  44. Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497CrossRefPubMedGoogle Scholar
  45. Kuroiwa Y, Kasinathan P, Choi YJ, Naeem R, Tomizuka K, Sullivan EJ, Knott JG, Duteau A, Goldsby RA, Osborne BA, Ishida I, Robl JM (2002) Cloned transchromosomic calves producing human immunoglobulin. Nat Biotechnol 20:889–894CrossRefPubMedGoogle Scholar
  46. Kuroiwa Y, Kasinathan P, Matsushita H, Sathiyaselan J, Sullivan EJ, Kakitani M, Tomizuka K, Ishida I, Robl JM (2004) Sequential targeting of the genes encoding immunoglobulin-mu and prion protein in cattle. Nat Genet 36:775–780CrossRefPubMedGoogle Scholar
  47. Ladhani S (2003) Understanding the mechanism of action of the exfoliative toxins of Staphylococcus aureus. FEMS Immunol Med Microbiol 39:181–189CrossRefPubMedGoogle Scholar
  48. Lanning D, Sethupathi P, Rhee KJ, Zhai SK, Knight KL (2000) Intestinal microflora and diversification of the rabbit antibody repertoire. J Immunol 165:2012–2019PubMedGoogle Scholar
  49. Lee J, Fenton BM, Koch CJ, Frelinger JG, Lord EM (1998) Interleukin 2 expression by tumor cells alters both the immune response and the tumor microenvironment. Cancer Res 58:1478–1485PubMedGoogle Scholar
  50. Leonard JP, Coleman M, Ketas J, Ashe M, Fiore JM, Furman RR, Niesvizky R, Shore T, Chadburn A, Horne H, Kovacs J, Ding CL, Wegener WA, Horak ID, Goldenberg DM (2005) Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 23:5044–5051CrossRefPubMedGoogle Scholar
  51. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM (2005) Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell 7:301–311CrossRefPubMedGoogle Scholar
  52. Lobo ED, Hansen RJ, Balthasar JP (2004) Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci 93:2645–2668CrossRefPubMedGoogle Scholar
  53. Lonberg N (2005) Human antibodies from transgenic animals. Nat Biotechnol 23:1117–1125CrossRefPubMedGoogle Scholar
  54. Lu ZY, Brailly H, Wijdenes J, Bataille R, Rossi JF, Klein B (1995) Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments. Blood 86:3123–3131PubMedGoogle Scholar
  55. May LT, Neta R, Moldawer LL, Kenney JS, Patel K, Sehgal PB (1993) Antibodies chaperone circulating IL-6. J Immunol 151:3225–3236PubMedGoogle Scholar
  56. Michallet MC, Preville X, Flacher M, Fournel S, Genestier L, Revillard JP (2003) Functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. Transplantation 75:657–662CrossRefPubMedGoogle Scholar
  57. Mihara M, Koishihara H, Fukui K, Ohsugi YY (1991) Murine anti-human IL-6 monoclonal antibody prolongs the half-life in circulating blood and thus prolongs the bioactivity of human IL-6 in mice. Immunology 74:55–59PubMedGoogle Scholar
  58. Mina L, Sledage GW Jr (2006) Twenty years of systemic therapy of breast cancer. Oncology 20:25–32PubMedGoogle Scholar
  59. Montero-Julian FA, Gautherot E, Wijdenes J, Klein B, Brailly H (1994) Pharmacokinetics of interleukin-6 during therapy with anti-interleukin-6 monoclonal antibodies: enhanced clearance of interleukin-6 by a combination of three anti-interleukin-6 antibodies. J Interferon Res 14:301–302PubMedGoogle Scholar
  60. Novick RP (2003) Mobile genetic elements and bacterial toxinoses: the superantigen-encoding pathogenicity islands of Staphylococcus aureus. Plasmid 49:93–105CrossRefPubMedGoogle Scholar
  61. O'Riordan K, Lee JC (2004) Staphylococcus aureus capsular polysaccharides. Clin Microbiol Rev 17:218–234CrossRefPubMedGoogle Scholar
  62. Okum EJ, Perez-Tamayo RA, Higgins RS, Kasirajan V, Flattery M, Crowley S (2006) Administration of rabbit anti-thymocyte globulin during cardiopulmonary bypass: a novel approach to the highly sensitized cardiac transplant patient. J Heart Lung Transplant 25:608–610CrossRefPubMedGoogle Scholar
  63. Pendley C, Schantz A, Wagner C (2003) Immunogenicity of therapeutic antibodies. Curr Opin Mol Ther 5:172–179PubMedGoogle Scholar
  64. Preville X, Flacher M, LeMauff B, Beauchard S, Davelu P, Tiollier J, Revillard JP (2001) Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation 71:460–468CrossRefPubMedGoogle Scholar
  65. Rainey GJ, Young JAT (2004) Antitoxins: novel strategies to target agents of bioterrorism. Nat Rev Microbiol 2:721–726CrossRefPubMedGoogle Scholar
  66. Regan J, Campbell K, van Smith L, Pouletty P, Schroeder TJ, Guttmann RD, Buelow R (1997) Characterization of anti-thymoglobulin, anti-ATGAM, and anti-OKT3 IgG antibodies in human serum with an 11-min ELISA. Transpl Immunol 5:49–56CrossRefPubMedGoogle Scholar
  67. Reichert JM, Dewitz MC (2006) Anti-infective monoclonal antibodies: perils and promise of development. Nat Rev Drug Discov 5:191–195CrossRefPubMedGoogle Scholar
  68. Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC (2005) Monoclonal antibody successes in the clinic. Nat Biotechnol 23:1073–1078CrossRefPubMedGoogle Scholar
  69. Rhode H, Knobloch JK, Horstkotte MA, Mack D (2001) Correlation of Staphylococcus aureus icaADBC genotype and biofilm expression phenotype. J Clin Microbiol 39:4595–4596CrossRefGoogle Scholar
  70. Ringleb PA (2006) Thrombolytics, anticoagulants, and antiplatelet agents. Stroke 37:312–313CrossRefPubMedGoogle Scholar
  71. Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA, Khazaeli MB, Saleh MN, Carey D, LoBuglio AF, Wheeler RH, Cooper MR, Waksal HW (2001) Phase I study of anti-epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol 19:3234–3243PubMedGoogle Scholar
  72. Sapra P, Allen TM (2004) Improved outcome when B-cell lymphoma is treated with combination of immunoliposomal anticancer drugs targeted to both the CD18 and CD20 epitopes. Clin Cancer Res 10:2530–2537CrossRefPubMedGoogle Scholar
  73. Sato TA, Widmer MB, Finkelman FD, Madani H, Jacobs CA, Grabstein KH, Maliszewski CR (1993) Recombinant soluble murine IL-4 receptor can inhibit or enhance IgE responses in vivo. J Immunol 150:2717PubMedGoogle Scholar
  74. Schafer R, Sheil JM (1995) Superantigens and their role in infectious disease. Adv Pediatr Infect Dis 10:369–390PubMedGoogle Scholar
  75. Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, Xie D, Lai J, Stadlen A, Li B, Fox JA, Presta LG (2001) High resolution mapping of the binding site of human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII and FcRn and designs of IgG1 variants with improved biding to the FC gamma R. J Biol Chem 276:6591–6604CrossRefPubMedGoogle Scholar
  76. Simpson KH, Bowden G, Hook M, Anvari B (2003) Measurement of adhesive forces between individual Staphylococcus aureus MSCRAMMs and protein-coated surfaces by use of optical tweezers. J Bacteriol 185:2031–2035CrossRefPubMedGoogle Scholar
  77. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792CrossRefPubMedGoogle Scholar
  78. Srinivasan A, Dick JD, Perl TM (2002) Vancomycin resistance in Staphylococci. Clin Microbiol Rev 15:430–438CrossRefPubMedGoogle Scholar
  79. Stein R, Zhengxing Q, Chen S, Rosario A, Shi V, Hayes M, Horak ID, Hansen HJ, Goldenberg DM (2004) Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma. Clin Cancer Res 10:2868–2878CrossRefPubMedGoogle Scholar
  80. Sunada H, Magun BE, Mendelson J, MacLeod CL (1986) Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci USA 83:3825–3829CrossRefPubMedGoogle Scholar
  81. Tomlinson A, Zitener HJ (1993) Enhancement of the biologic effects of interleukin-3 in vivo by anti-interleukin-3 antibodies. Blood 82:1133Google Scholar
  82. Tulpule A (2005) Multidrug resistance in AIDS-related lymphoma. Curr Opin Oncol 17:466–468CrossRefPubMedGoogle Scholar
  83. Umana P, Jean-Maret J, Moudry R, Amstutz H, Bailey JE (1999) Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol 17:176–180CrossRefPubMedGoogle Scholar
  84. Vasir JK, Labhasetwar V (2005) Targeted drug delivery in cancer therapy. Technol Cancer Res Treat 4:363–374PubMedGoogle Scholar
  85. Vidal L, Attard G, Kaye S, De Bono J (2004) Reversing resistance to targeted therapy. J Chemother 26(4):7–12Google Scholar
  86. Vincent M (2006) Tesmilifene may enhance breast cancer chemotherapy by killing a clone of aggressive, multi-drug resistant cells through its action on the p-glycoprotein pump. Med Hypotheses 66:715–7131CrossRefPubMedGoogle Scholar
  87. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA, Fisher RI (2001) Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 19:389–397PubMedGoogle Scholar
  88. Wann ER, Pohlmann-Dietze P, Steinhuber A, Chien YT, Manna A, van Wamel W, Cheung A (2000) Agr-independent regulation of fibronectin-binding protein(s) by the regulatory locus sar in Staphylococcus aureus. Mol Microbiol 36:230–243CrossRefGoogle Scholar
  89. Webster A, Pankhurst T, Rinaldi F, Chapman JR, Craig JC (2006) Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients. Cochrane Database Syst Rev 2:CD004756PubMedGoogle Scholar
  90. Weill JC, Reynaud CA (1996) Rearrangement/hypermutation/gene conversion: when, where and why? Immunol Today 17:92–97CrossRefPubMedGoogle Scholar
  91. Weng WK, Levy R (2003) Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 21:3940–3947CrossRefPubMedGoogle Scholar
  92. Wiberg FC, Rasmussen SK, Frandsen TP, Rasmussen LK, Tengbjerg K, Coljee VW, Sharon J, Yang CY, Bregenholt S, Nielsen LS, Haurum JS, Tostrup AB (2006) Production of target-specific recombinant human polyclonal antibodies in mammalian cells. Biotechnol Bioeng 94:396–405CrossRefPubMedGoogle Scholar
  93. Wu AM, Senter PD (2005) Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 23:1137–1146CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Therapeutic Human Polyclonals Inc.Mountain ViewUSA

Personalised recommendations