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  • Review Article
  • Published:

Potent antibody therapeutics by design

Nature Reviews Immunology volume 6, pages 343–357 (2006)Cite this article

This article has been updated

Key Points

  • Antibody therapeutics have become an important new drug class, with 17 antibodies now marketed for therapeutic use in the United States across diverse clinical settings: oncology, chronic inflammatory diseases, transplantation, infectious diseases and cardiovascular medicine.

  • Three powerful factors are converging to support the emergence of antibody therapeutics that are more potent and effective: a clinical imperative to achieve a better outcome for patients; the availability of established and emerging technologies to improve antibody performance; and the commercial drive to compete. Increased competition is inevitable, because many approved antibody drugs and antibody drugs under investigation target the same antigen and clinical indications.

  • Antibodies have numerous interdependent properties that can be tuned to improve their clinical potential. These include immunogenicity, antigen-binding specificity and affinity, effector functions and other biological activities, pharmacokinetics, molecular architecture, internalization after cell binding, and biophysical characteristics. Several of these properties can be modulated by engineering the interaction between IgG and one of its binding partners: that is, target antigen, IgG receptors (FcγRs), complement component 1q (C1q) and the salvage receptor FcRn.

  • Antibodies are commonly optimized by selection from genetically diverse display libraries of antibody-fragment variants. Alternatively, they can be optimized by structure-based design followed by expression, purification and functional characterization of individual variants. These selection and design strategies are complementary and are particularly powerful when used in combination.

  • The first major success in the design of antibodies for therapy was the advent of chimerization and humanization to address immunogenicity and other limitations of mouse monoclonal antibodies. Numerous high-potency humanized and human antibodies are now in preclinical and clinical development.

Abstract

Antibodies constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The generation of potent antibody therapeutics, which I review here, is an iterative design process that involves the generation and optimization of antibodies to improve their clinical potential.

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Figure 1: Iterative design of antibody therapeutics.
Figure 2: IgG structure and function.
Figure 3: Representative antibody formats.

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Change history

  • 18 April 2006

    Table 1 in this article has been amended. A new PDF has replaced the previous version.

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Acknowledgements

I thank P. Senter for critical comment on this manuscript, C. McDonagh and B. Toki for help with figure 2, and P. Umaña and N. Damle for sharing unpublished observations.

In Table 1 and S1 of the AOP version of this article, Avastin was incorrectly noted to be an approved treatment for head and neck cancer. Instead, Erbitux is approved for treatment of these cancers. This error has since been corrected in the HTML and PDF versions of this article and will appear correctly in the May 2006 print issue.

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  1. Department of Antibody Technologies, Seattle Genetics Incorporated, 21823 30th Drive South East, Bothell, 98021, Washington, USA

    Paul J. Carter

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Glossary

Adverse event

An untoward medical occurrence in a patient who has been administered a pharmaceutical product. This occurrence does not necessarily have a causal relationship with the treatment.

Partial response

In oncology, a response in which there is greater than or equal to a 50% reduction in total tumour size, with no new lesions or increase in size of an existing lesion. This is often calculated as the sum of the products of the perpendicular diameters of all measurable lesions.

Complete response

In oncology, a response in which no remaining tumour can be detected by visual inspection or by clinical imaging technologies. This does not necessarily indicate that the disease has been cured.

Response duration

The time from the first response until disease progression or death.

Effector functions

Fc-mediated antibody properties that are involved in the destruction of target cells: that is, antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP).

Half-life

The time taken for the plasma concentration of a drug to decrease to half of its original value. Initial half-life and terminal half-life refer to the first (distribution) and second (elimination) phases of bi-exponential pharmacokinetics, respectively.

Complementarity-determining regions

(CDRs). The polypeptide loops in an antibody that are the main determinants of antigen binding. There are three CDRs in the variable domain of the immunoglobulin heavy chain and three in the variable domain of the immunoglobulin light chain.

Binding affinity

(Kd). For two interacting molecules, the ratio of their association (ka) and dissociation (kd) rate constants: that is, Kd = kd/ka.

Framework regions

The polypeptide segments in an antibody that together form a structural scaffold for presentation of the antigen-binding (complementarity-determining region) loops. There are four framework regions in the variable domain of the immunoglobulin heavy chain and four in the variable domain of the immunoglobulin light chain.

Phage-display technology

A technology for displaying a protein, such as an antibody fragment, on the surface of a bacteriophage that contains the gene(s) encoding the displayed protein(s), thereby physically linking the genotype and phenotype.

Affinity maturation

An in vitro or in vivo process for increasing the affinity of a binding interaction, such as that between an antibody and its cognate antigen.

Species crossreactive

For antibodies, this is often used to denote binding to the corresponding antigen from two or more species: for example, humans, non-human primates and rodents.

Single-chain V-domain antibody fragment

(scFv). A small antibody fragment that comprises the variable (V) domains of the immunoglobulin heavy and light chain in either order joined by a short (∼15 amino-acid residue) peptide linker.

Functional display-library size

The number of clones that is displayed with sufficient efficiency to be potentially selectable.

Epitope

The part of an antigen that interacts with an antibody.

Severe combined immunodeficient mice

(SCID mice). Mice that are homozygous for the scid allele of the gene that encodes the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). These mice are severely deficient in functional B and T cells.

PEGylation

The chemical modification of a protein by conjugation to one or more molecules of polyethylene glycol (PEG).

Valency

For antibodies, the number of binding sites for the cognate antigen.

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Carter, P. Potent antibody therapeutics by design. Nat Rev Immunol 6, 343–357 (2006). https://doi.org/10.1038/nri1837

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