Therapeutic monoclonal antibodies

doi:10.1016/S0140-6736(00)01034-5

The Lancet

Volume 355, Issue 9205, 26 February 2000, Pages 735-740

https://doi.org/10.1016/S0140-6736(00)01034-5 Get rights and content

Summary

The therapeutic potential of monoclonal antibodies (mAb) was quickly realised after the hybridoma technique allowed their development in the mid 1970s. Chimeric humanised and fully humanised mAb can now be made by recombinant engineering. About a quarter of all biotech drugs in development are mAb, and around 30 products are in use or being investigated. Licensed products are available for inhibition of alloimmune and autoimmune reactivity, and for antitumour, antiplatelet, or antiviral therapy. Short-term side-effects are tolerable and as expected, although long-term safety remains to be elucidated. The cost-effectiveness and quality-of-life benefits of the use of mAb in patients who are usually seriously and chronically ill also needs studying. The therapeutic use of mAb is now established, and is perhaps the first example of how the “new biology” and the understanding of underlying molecular mechanisms has benefited patients.

Section snippets

mAb structure and function

Immunoglobulins consist of two light and two heavy chains composed of different domains (figure). The Fab domain serves as the antigen-binding site; it is made of heavy and light variable chains. The complementarity-determining regions of the variable chains define the binding site, the structure which is complementary to the epitope on the antigen that can be bound by the antibody. Antibodies achieve diversity due to variations in the aminoacid sequences of the complementarity-determining

Factors regulating mAb-based targeted therapies

Several obstacles to achieving efficacy have been identified for this therapeutic strategy which attempts to induce an unprecedented degree of targeting specificity while using large proteins whose sizes greatly exceed those of conventional drugs. mAb are large proteins and thereby have slower kinetics of distribution than small molecules and more limited tissue-penetration properties. The ability of mAb to penetrate cancers or sites of inflammation is low.3, 4 Particularly in the case of

Biological responses

Efficacy of any particular mAb depends on several variables. These include the characteristics of the targeted antigen, its function, its cell-surface density and tissue distribution, as well as characteristics of the mAb including fine specificity, avidity, and isotype. The mechanism(s) by which mAb achieve therapeutic effects is often not completely known. Potential mechanisms include: blocking or steric hindrance of the function of the target antigen; cytoxocity to the cell expressing the

Side-effects

Potential adverse events may be related to one of three mechanisms: the xenogenetic nature of the mAb used, especially when the mAb is administered without associated immunosuppression; suppression of physiological functions in line with the specificity of the mAb; and activation of inflammatory cells or mediators after binding of the mAb to its target. Sensitisation has been regularly observed in human beings treated with mAb. However, with the mAb so far studied, hypersensitivity reactions

Current treatments with mAb

The potential therapeutic application of mAb created a tremendous interest in the medical and pharamaceutical community. A recent survey suggested that over a quarter of all biotech drugs in development are mAb. Within this group more than 30 chimeric, humanised, or fully human antibodies account for more than 30 products being routinely used or investigated in the clinic for various indications.

The most promising and advanced therapeutic strategies include inhibition of alloimmune and

Conclusions

The initial clinical studies with mAb identified several areas that promise to make significant contributions to the management of patients with various diseases. The promising results of the mAb discussed here represent the most advanced clinical antibody therapy programmes, but a large number of innovative strategies with recombinantly prepared mAb with novel effector functions are in earlier stages of clinical evaluation. Such studies are being done in most clinical disciplines. The ability

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View all citing articles on Scopus

View full text

New Drug ClassesTherapeutic monoclonal antibodies

Summary

Section snippets

mAb structure and function

Factors regulating mAb-based targeted therapies

Biological responses

Side-effects

Current treatments with mAb

Conclusions

Lancet

Lancet

Lancet

Continuous cultures of fused cells secreting antibody of predefined specificity

Nature

In vivo and in vitro production of monoclonal antibodies: current possibilities and future perspectives

Res Immunol

Percentage of anti-CD4 monoclonal antibody-coated lymphocytes in the rheumatoid joint is associated with clinical improvement: implications for the development of immunotherapeutic dosing regimens

Arthritis Rheum

An overview of monoclonal antibody therapy of cancer

Semin Oncol

How do monoclonal antibodies induce tolerance? A role for infectious tolerance?

Annu Rev Immunol

Effect of a single amino acid mutation on the activating and immunosuppressive properties of a “humanised” OKT3 monoclonal antibody

J Immunol

In vivo generation of C4d, Bb, iC3v, and SC5b-9 after OKT3 administration in kidney and lung transplant recipients

Transplantation

A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants

N Engl J Med

Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody

Transplantation

A phase I trial of humanized anti-interleukin 2 receptor antibody in renal transplantation

Transplantation

Reduction of acute renal allograft rejection by daclizumab: Daclizumab Double Therapy Study Group

Transplantation

Anti-tumor necrosis factor-α therapy in rheumatoid arthritis

Adv Immunol

Tumor necrosis factor and CD

Gut

New Drug Classes
Therapeutic monoclonal antibodies