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  • Review Article
  • Published:

Therapeutic antibodies for human diseases at the dawn of the twenty-first century

Nature Reviews Drug Discovery volume 2, pages 52–62 (2003)Cite this article

A Correction to this article was published on 01 March 2003

Key Points

  • At present there are approximately 200 antibodies in clinical trials, and the US Food and Drug Administration has approved several antibodies against cancer, transplant rejection, rheumatoid arthritis, Crohn's disease and antiviral prophylaxis. As the development of new therapeutic reagents into commercial products takes about 10 years, today's approved antibodies are generally mouse, chimeric or humanized antibodies, whereas the more recently developed reagents in clinical trials are typically complete human antibodies, of which some are derived from in vitro antibody libraries and transgenic mice.

  • The efficacy of antibodies in the prophylaxis and treatment of infectious diseases is likely to increase if a polyclonal human serum therapy is mimicked — that is, if a pool of highly specific and high-affinity monoclonal antibodies are administered.

  • In cancer therapy, the purpose of antibody administration is specific cancer-cell destruction or starving of tumours through taregting of the tumour vasculature. New technologies in the panning of antibody libraries on intact cells have made it possible to isolate antibodies to novel and promising cancer-specific and cancer-associated antigens.

  • Together with cancer, inflammatory and autoimmune diseases are an important focus for antibody therapy. Antibodies have been developed to bind specific cytokines or their receptors for the purpose of inhibiting the detrimental effect of the cytokine. Inhibition of cytokines associated with inflammation and the modulation of the immune response by immune-cell depletion has been shown to be a viable therapy in autoimmune diseases.

  • Small antibody fragments, such as single-chain Fv and Fab fragments, can do part of the job normally done by intact antibodies, such as blocking the action of a toxin or the ligand–receptor interaction, or inhibiting infection isuch as viral diseases. Antibody fragments can carry many different types of molecule to their targets as an effector moiety.

  • Bispecific antibodies have the ability to bind to two different antigens and have been used to cross-link various cells and molecules. Bispecific antibodies have primarily been used to been to re-direct effector cells to target cells.

  • A prerequisite for effective targeting is that antibodies should be able to penetrate tissues. Small antibody fragments are better than complete antibodies in this respect. However, small antibody fragments show rapid clearance from the circulation, and the fraction of the injected dose that reaches its target is at present too low, even for bivalent fragments. Therefore, manipulations to control antibody pharmacokinetics will be crucial for the success of therapeutic antibody fragments.

Abstract

Antibodies are highly specific, naturally evolved molecules that recognize and eliminate pathogenic and disease antigens. The past 30 years of antibody research have hinted at the promise of new versatile therapeutic agents to fight cancer, autoimmune diseases and infection. Technology development and the testing of new generations of antibody reagents have altered our view of how they might be used for prophylactic and therapeutic purposes. The therapeutic antibodies of today are genetically engineered molecules that are designed to ensure high specificity and functionality. Some antibodies are loaded with toxic modules, whereas others are designed to function naturally, depending on the therapeutic application. In this review, we discuss various aspects of antibodies that are relevant to their use as as therapeutic agents.

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Figure 1: The modular structure of immunoglobulins.
Figure 2: Antibody engineering.
Figure 3: In vitro and in vivo human antibody techniques exemplified by phage display and transgenic mouse technologies.
Figure 4: Natural immunoglobulin effector functions.
Figure 5: Different formats of antibody fragment.

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Authors and Affiliations

  1. Affitech AS, Gaustadalleen 21, Oslo, N-0349, Norway

    Ole Henrik Brekke

  2. Department of Biology, University of Oslo, N-0349, Norway

    Inger Sandlie

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  1. Ole Henrik Brekke
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Correspondence to Ole Henrik Brekke.

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DATABASES

Cancer.gov

actue myeloid leukemia

breast cancer

lung cancer

non-Hodgkin's lymphoma

non-small-cell lung cancer

LocusLink

Epidermal growth factor receptor

ERBB2

MUC1

SDC1 webbody

OMIM

Crohn's disease

rheumatoid arthritis

FURTHER INFORMATION

ClinicalTrials.gov

Cambridge Antibody Technology

Glossary

IMMUNOGLOBULIN DOMAIN

Compactly folded globular units of approximately 110 amino acids that comprise immunoglobulin heavy and light chains.

CYTOKINES

A class of small proteins released by one cell that affects the physiology of other cells locally and systemically in a particular fashion through binding to a specific receptor.

EFFECTOR FUNCTIONS

The antigen-elimination processes mediated by immunoglobulins and initiated by the binding of effector molecules to the Fc part of the immunoglobulin. The common effector functions are complement-dependent cytotoxicity (CDC), phagocytosis and antibody-dependent cellular cytotoxicity (ADCC).

COMPLEMENT-DEPENDENT CYTOTOXICITY

Once bound to antigen, both IgM and IgG can trigger a sequence of reactions by which serum proteins called complement factors are cleaved. One of the results is destruction of the target cell through complement-dependent cytotoxicity.

PROGRAMMED CELL DEATH

Programmed cell death infers that cells are determined to die at a specific stage of development or having received a specific signal. The process is known as apoptosis. The cells shrivel and are engulfed by nearby phagocytic cells without eliciting any inflammatory response.

HYBRIDOMA

An antibody-secreting B-cell line that is generated by fusing splenic-derived B cells with a plasmacytoma. A hybridoma produces the same antibody as the parent B cell and divides and grows in culture like the parent cancer cell. The antibody produced is monoclonal.

SERUM THERAPY

The treatment of an infectious disease with the serum from an immunized animal or individual, and which contains antibody.

POST-EXPOSURE PROPHYLAXIS

A treatment that is designed to protect an individual against a disease agent to which the individual has been recently exposed.

PEGYLATION

The covalent attachment of the polymeric molecule poly-ethylene glycol (PEG) to proteins.

TROYBODY

An antibody with specificity for an antigen-presenting cell and with an antigenic fragment inserted into a constant domain.

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Brekke, O., Sandlie, I. Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov 2, 52–62 (2003). https://doi.org/10.1038/nrd984

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