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Therapeutic antibodies for autoimmunity and inflammation

Nature Reviews Immunology volume 10, pages 301–316 (2010)Cite this article

Subjects

Key Points

  • First-generation therapeutic antibodies have provided valuable lessons. A large number of therapeutic antibodies using diverse platforms have provided valuable insights into the strengths and limitations of each technology platform.

  • The mechanisms by which therapeutic antibodies mediate their functions are diverse.

  • Therapeutic antibodies operate through distinct mechanisms of action that affect their pharmacodynamic properties and biological activities.

  • Effector function modifications can be used to optimize desired activities of a therapeutic antibody.

  • Increased and decreased binding affinities to Fc receptors for IgG (FcγRs), complement components and neonatal FcR can be used to optimize desired activities of therapeutic antibodies.

  • Bispecific and multispecific antibodies enhance therapeutic applications.

  • The development of multi-antigen-binding therapeutic antibodies enhances their therapeutic potential.

Abstract

The development of therapeutic antibodies has evolved over the past decade into a mainstay of therapeutic options for patients with autoimmune and inflammatory diseases. Substantial advances in understanding the biology of human diseases have been made and tremendous benefit to patients has been gained with the first generation of therapeutic antibodies. The lessons learnt from these antibodies have provided the foundation for the discovery and development of future therapeutic antibodies. Here we review how key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibodies with promise for greater clinical efficacy and safety.

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Figure 1: Engineering IgG structure and function.
Figure 2: Mechanisms of action of therapeutic antibodies.
Figure 3: Modular IgG architecture supports numerous bispecific antibody formats.

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Authors and Affiliations

  1. Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Andrew C. Chan

  2. Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, 94080, California, USA

    Paul J. Carter

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A.C.C. and P.J.C. are employees of Genentech, Inc.

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Glossary

Effector functions

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

Half-life

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

Phage display

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

Binding affinity

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

Neonatal FcR

(FcRn). An Fc receptor that is structually related to MHC class I molecules and protects IgG from degradation, resulting in long serum half-life. Additionally, FcRn mediates IgG transfer from a mother to her fetus, thereby providing passive immunity.

Immunoadhesin

A fusion protein that combines the functional domain of a binding protein, such as a receptor or ligand, with an immunoglobulin Fc domain. Such Fc fusion proteins can endow binding proteins with antibody-like properties including long serum half-life and effector functions.

Human anti-chimeric antibodies

(HACAs). The immune system can develop an antibody response to chimeric antibodies. Binding of HACAs to chimeric antibodies forms immune complexes that can shorten the half-life of the therapeutic antibodies and compromise clinical effectiveness. Additionally these immune complexes can deposit in organs such as skin and kidney causing adverse events, including rashes and glomerulonephritis.

Human anti-human antibodies

(HAHAs). The immune system can also develop an immune response to human therapeutic antibodies. HAHAs tend to be less common and less severe than HACAs.

Bispecific antibodies

Antibodies capable of binding to two different antigens or two distinct epitiopes on the same antigen are known as bispecific.

Exposure

In the pharmacokinetic sense, the area under the curve for a plot of drug concentration versus time.

Valency

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

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Chan, A., Carter, P. Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol 10, 301–316 (2010). https://doi.org/10.1038/nri2761

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