Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Development trends for human monoclonal antibody therapeutics

Nature Reviews Drug Discovery volume 9, pages 767–774 (2010)Cite this article

Subjects

Abstract

Fully human monoclonal antibodies (mAbs) are a promising and rapidly growing category of targeted therapeutic agents. The first such agents were developed during the 1980s, but none achieved clinical or commercial success. Advances in technology to generate the molecules for study — in particular, transgenic mice and yeast or phage display — renewed interest in the development of human mAbs during the 1990s. In 2002, adalimumab became the first human mAb to be approved by the US Food and Drug Administration (FDA). Since then, an additional six human mAbs have received FDA approval: panitumumab, golimumab, canakinumab, ustekinumab, ofatumumab and denosumab. In addition, 3 candidates (raxibacumab, belimumab and ipilimumab) are currently under review by the FDA, 7 are in Phase III studies and 81 are in either Phase I or II studies. Here, we analyse data on 147 human mAbs that have entered clinical study to highlight trends in their development and approval, which may help inform future studies of this class of therapeutic agents.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Percentage of four types of mAbs in clinical development during the periods 1990–1999 and 2000–2008.
Figure 2: Cumulative number of human mAbs entering clinical study between 1985 and 2008.
Figure 3: Transition rates between clinical phases for human mAbs.

References

  1. Reichert, J. M. Monoclonal antibodies as innovative therapeutics. Curr. Pharm. Biotechnol. 9, 423–430 (2008).

    Article  CAS  Google Scholar 

  2. Reichert, J. M., Rosensweig, C. J., Faden, L. B. & Dewitz, M. C. Monoclonal antibody successes in the clinic. Nature Biotech. 23, 1073–1078 (2005).

    Article  CAS  Google Scholar 

  3. Reichert, J. M. Antibodies to watch in 2010. MAbs 2, 84–100 (2010).

    Article  Google Scholar 

  4. James, K. & Bell, G. T. Human monoclonal antibody production. Current status and future prospects. J. Immunol. Methods 100, 5–40 (1987).

    Article  CAS  Google Scholar 

  5. Olsson, L. & Kaplan, H. S. Human–human hybridomas producing monoclonal antibodies of predefined antigenic specificity. Proc. Natl Acad. Sci. USA 77, 5429–5431 (1980).

    Article  CAS  Google Scholar 

  6. Shoenfeld, Y. et al. Production of autoantibodies by human–human hybridomas. J. Clin. Invest. 70, 205–208 (1982).

    Article  CAS  Google Scholar 

  7. Olsson, L. et al. Antibody producing human–human hybridomas. II. Derivation and characterization of an antibody specific for human leukemia cells. J. Exp. Med. 159, 537–550 (1984).

    Article  CAS  Google Scholar 

  8. Kozbor, D. & Roder, J. C. Requirements for the establishment of high-titered human monoclonal antibodies against tetanus toxoid using the Epstein–Barr virus technique. J. Immunol. 127, 1275–1280 (1981).

    CAS  PubMed  Google Scholar 

  9. Kozbor, D., Lagarde, A. E. & Roder, J. C. Human hybridomas constructed with antigen-specific Epstein–Barr virus-transformed cell lines. Proc. Natl Acad. Sci. USA 79, 6651–6655 (1982).

    Article  CAS  Google Scholar 

  10. Beerli, R. R. & Rader, C. Mining human antibody repertoires. MAbs 2, 361–374 (2010).

    Article  Google Scholar 

  11. Teng, N. N. et al. Protection against Gram-negative bacteremia and endotoxemia with human monoclonal IgM antibodies. Proc. Natl Acad. Sci. USA 82, 1790–1794 (1985).

    Article  CAS  Google Scholar 

  12. Ziegler, E. J. et al. Treatment of Gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N. Engl. J. Med. 324, 429–436 (1991).

    Article  CAS  Google Scholar 

  13. Cross, A. S. Antiendotoxin antibodies: a dead end? Ann. Intern. Med. 121, 58–60 (1994).

    Article  CAS  Google Scholar 

  14. Luce, J. M. Introduction of new technology into critical care practice: a history of HA-1A human monoclonal antibody against endotoxin. Crit. Care Med. 21, 1233–1241 (1993).

    Article  CAS  Google Scholar 

  15. McCloskey, R. V., Straube, R. C., Sanders, C., Smith, S. M. & Smith, C. R. Treatment of septic shock with human monoclonal antibody HA-1A. A randomized, double-blind, placebo-controlled trial. CHESS Trial Study Group. Ann. Intern. Med. 121, 1–5 (1994).

    Article  CAS  Google Scholar 

  16. Abbott. Abbott Annual Report 2008. Abbott website [online], (2008).

  17. US Food and Drug Administration. Vectibix Panitumumab Injectable. Application No.: 125147. Medical Review(s). FDA website [online], (2006).

  18. Van Cutsem, E. et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J. Clin. Oncol. 25, 1658–1664 (2007).

    Article  CAS  Google Scholar 

  19. Mazumdar, S. & Greenwald, D. Golimumab. MAbs 1, 422–431 (2009).

    Article  Google Scholar 

  20. Lachmann, H. J. et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N. Engl. J. Med. 360, 2416–2425 (2009).

    Article  CAS  Google Scholar 

  21. Dhimolea, E. Canakinumab. MAbs 2, 3–13 (2010).

    Article  Google Scholar 

  22. Cingoz, O. Ustekinumab. MAbs 1, 216–221 (2009).

    Article  Google Scholar 

  23. Teeling, J. L. et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J. Immunol. 177, 362–371 (2006).

    Article  CAS  Google Scholar 

  24. Glennie, M. J., French, R. R., Cragg, M. S. & Taylor, R. P. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol. Immunol. 44, 3823–3837 (2007).

    Article  CAS  Google Scholar 

  25. Zhang, B. Ofatumumab. MAbs 1, 326–331 (2009).

    Article  Google Scholar 

  26. Pageau, S. C. Denosumab. MAbs 1, 210–215 (2009).

    Article  Google Scholar 

  27. Mazumdar, S. Raxibacumab. MAbs 1, 531–538 (2009).

    Article  Google Scholar 

  28. Dall'Era, M. & Wofsy, D. Connective tissue diseases: belimumab for systemic lupus erythematosus: breaking through? Nature Rev. Rheumatol. 6, 124–125 (2010).

    Article  CAS  Google Scholar 

  29. Wallace, D. J. et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 61, 1168–1178 (2009).

    Article  CAS  Google Scholar 

  30. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  Google Scholar 

  31. Reichert, J. M. & Dewitz, M. C. Anti-infective monoclonal antibodies: perils and promise of development. Nature Rev. Drug Discov. 5, 191–195 (2006).

    Article  CAS  Google Scholar 

  32. Reichert, J. M. & Valge-Archer, V. E. Development trends for monoclonal antibody cancer therapeutics. Nature Rev. Drug Discov. 6, 349–356 (2007).

    Article  CAS  Google Scholar 

  33. Green, L. L. et al. Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs. Nature Genet. 7, 13–21 (1994).

    Article  CAS  Google Scholar 

  34. Lonberg, N. et al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368, 856–859 (1994).

    Article  CAS  Google Scholar 

  35. Green, L. L. Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies. J. Immunol. Methods 231, 11–23 (1999).

    Article  CAS  Google Scholar 

  36. Lonberg, N. Human antibodies from transgenic animals. Nature Biotech. 23, 1117–1125 (2005).

    Article  CAS  Google Scholar 

  37. McCafferty, J., Griffiths, A. D., Winter, G. & Chiswell, D. J. Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348, 552–554 (1990).

    Article  CAS  Google Scholar 

  38. Vaughan, T. J. et al. Human antibodies with sub-nanomolar affinities isolated from a large non-immunized phage display library. Nature Biotech. 14, 309–314 (1996).

    Article  CAS  Google Scholar 

  39. Clackson, T., Hoogenboom, H. R., Griffiths, A. D. & Winter, G. Making antibody fragments using phage display libraries. Nature 352, 624–628 (1991).

    Article  CAS  Google Scholar 

  40. Chirino, A. J., Ary, M. L. & Marshall, S. A. Minimizing the immunogenicity of protein therapeutics. Drug Discov. Today 9, 82–90 (2004).

    Article  CAS  Google Scholar 

  41. Baert, F. et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601–608 (2003).

    Article  CAS  Google Scholar 

  42. De Groot, A. S. & Scott, D. W. Immunogenicity of protein therapeutics. Trends Immunol. 28, 482–490 (2007).

    Article  CAS  Google Scholar 

  43. Bartelds, G. M. et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann. Rheum. Dis. 66, 921–926 (2007).

    Article  CAS  Google Scholar 

  44. Bender, N. K. et al. Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol. Int. 27, 269–274 (2007).

    Article  CAS  Google Scholar 

  45. Hwang, W. Y. & Foote, J. Immunogenicity of engineered antibodies. Methods 36, 3–10 (2005).

    Article  CAS  Google Scholar 

  46. Saif, M. W. & Cohenuram, M. Role of panitumumab in the management of metastatic colorectal cancer. Clin. Colorectal Cancer 6, 118–124 (2006).

    Article  CAS  Google Scholar 

  47. Saif, M. W., Peccerillo, J. & Potter, V. Successful re-challenge with panitumumab in patients who developed hypersensitivity reactions to cetuximab: report of three cases and review of literature. Cancer Chemother. Pharmacol. 63, 1017–1022 (2009).

    Article  Google Scholar 

  48. Chung, C. H. et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose. N. Engl. J. Med. 358, 1109–1117 (2008).

    Article  CAS  Google Scholar 

  49. Lecluse, L. L. A. et al. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch. Dermatol. 146, 127–132 (2010).

    Article  CAS  Google Scholar 

  50. Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

    Article  CAS  Google Scholar 

  51. Nechansky, A. HAHA — nothing to laugh about. Measuring the immunogenicity (human anti-human antibody response) induced by humanized monoclonal antibodies applying ELISA and SPR technology. J. Pharm. Biomed. Anal. 51, 252–254 (2009).

    Article  Google Scholar 

  52. Lofgren, J. A. et al. Comparing ELISA and surface plasmon resonance for assessing clinical immunogenicity of panitumumab. J. Immunol. 178, 7467–7472 (2007).

    Article  CAS  Google Scholar 

  53. Jefferis, R. & LeFranc, M.-P. Human immunoglobulin allotypes — possible implications for immunogenicity. MAbs 1, 332–338 (2009).

    Article  Google Scholar 

  54. Gilles, J. G. et al. Natural autoantibodies and anti-idiotypes. Semin. Thromb. Hemost. 26, 151–155 (2000).

    Article  CAS  Google Scholar 

  55. Emmi, L. The role of intravenous immunoglobulin therapy in autoimmune and inflammatory disorders. Neurol. Sci. 23 (Suppl. 1), 1–8 (2002).

    Article  Google Scholar 

  56. Harding, F. A. et al. The immunogenicity of humanized and fully human antibodies: residual immunogenicity residues in the CDR regions. Mabs 2, 256–265 (2010).

    Article  Google Scholar 

  57. Shankar, G., Pendley, C. & Stein, K. E. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nature Biotech. 25, 555–561 (2007).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Janice M. Reichert

    Present address: Janice M. Reichert is at the Tufts Center for the Study of Drug Development, Suite 1100, 75 Kneeland Street, Boston, Massachusetts 02111, USA.,

  2. Aaron L. Nelson

    Present address: Aaron L. Nelson was previously at the Tufts University School of Medicine, Boston, Massachusetts 02118, USA. Present address: Novartis Institutes for Biomedical Research, Room 7226, 7th floor, 300 Technology Square, Cambridge, Massachusetts 02139, USA.,

Authors and Affiliations

  1. Eugen Dhimolea is at the Tufts University School of Medicine, 136 Harrison Avenue, Boston, Massachusetts 02111, USA.,

    Eugen Dhimolea

  2. Janice M. Reichert is at the Tufts Center for the Study of Drug Development, Suite 1100, 75 Kneeland Street, Boston, Massachusetts 02111, USA.,

    Aaron L. Nelson

Authors
  1. Aaron L. Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eugen Dhimolea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Janice M. Reichert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Janice M. Reichert.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Tufts Center for the Study of Drug Development

Glossary

Allotype

Antibody allotypes are defined by their polymorphism within the immunoglobulin heavy and light chains. Natural allelic genetic variation in the constant region of genes in humans may predispose a given patient to anti-drug antibody responses if the drug is a foreign allotype.

Ankylosing spondylitis

A chronic condition of unknown aetiology that is characterized by inflammation of the joints of the spine and pelvis. Disease progression may result in fusion of the joints.

Anti-idiotypic antibody

An antibody that targets the hypervariable antigen-binding domain of an exogenous immunoglobulin, including therapeutic monoclonal antibodies. As the constant regions are fairly conserved, with the exception of allotypic differences, many anti-immunoglobulin responses will be directed against the highly variable, antigen-binding domain.

Cryopyrin-associated periodic syndromes

(CAPS). A group of rare, inherited autoimmune disorders associated with over-secretion of interleukin-1 that may cause inflammation of the skin, eyes, bones, joints and meninges.

Phage-display technologies

A method involving the use of bacteriophages to select desirable antibody variable domains based on their binding properties.

Pre-transplant desensitization

In the recipient patient, reduction of antibody-producing cells or the amount of circulating antibodies that might target foreign tissue prior to transplantation of an organ.

Systemic lupus erythematosus

A chronic, inflammatory autoimmune disease affecting connective tissue throughout the body.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nelson, A., Dhimolea, E. & Reichert, J. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 9, 767–774 (2010). https://doi.org/10.1038/nrd3229

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd3229

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research