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Advances in antibody engineering for rheumatic diseases

Nature Reviews Rheumatology volume 15, pages 197–207 (2019)Cite this article

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Abstract

The advent of biologic therapies, particularly antibody therapeutics, has revolutionized the pharmacological treatment of many rheumatic diseases. Antibody discovery began with the immunization of mice for the production of rodent immunoglobulins, but advances in protein and genetic engineering have now made it possible to generate fully human antibodies, which are better tolerated by patients. For most clinical applications in rheumatology, antibodies have been used as blocking agents capable of neutralizing the function of pro-inflammatory proteins, such as TNF. The latest strategies involve antibody products armed with effector moieties, such as anti-inflammatory drugs or cytokines, or antibody products that are specific for multiple targets for the selective inhibition of inflammation at sites of disease. Antibodies are some of the best-selling drugs in the world, and with further advances in antibody development, engineering of armed antibodies and bispecific products will have an important role in the treatment of rheumatic diseases.

Key points

  • The advancement of technologies for antibody production and engineering culminated in the production of fully human antibodies as well as antibody derivatives.

  • Most antibody therapeutics approved for the treatment of rheumatic diseases function as sophisticated blocking and neutralizing agents.

  • Armed immunocytokines and antibody–drug conjugates combine targeting specificity and effector functions of antibodies with the immunological effect of their payloads.

  • Bispecific antibodies might treat rheumatic diseases by taking advantage of a variety of diverse antibody functions.

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Fig. 1: Antibody effector functions.
Fig. 2: Antibody structures.
Fig. 3: Timeline of antibody developments.
Fig. 4: Development from fully mouse to fully human antibodies.
Fig. 5: Production of fully human antibodies.
Fig. 6: Next-generation antibody formats.

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Reviewer information

Nature Reviews Rheumatology thanks R. Williams and R. Kontermann, for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zürich, Switzerland

    Anja S. Schmid & Dario Neri

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Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Dario Neri.

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Competing interests

D.N. declares that he is co-founder and shareholder of Philogen, a company that develops (inter alia) antibody–cytokine fusion proteins for the treatment of cancer and of chronic inflammation. A.S.S. declares no competing interests.

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Glossary

Antibody-dependent cell-mediated cytotoxicity

(ADCC). The crystallizable fragment (Fc)-receptor-mediated killing of antibody-coated target cells through immune recognition of the antibody Fc by effector cells such as natural killer cells.

Complement-dependent cytotoxicity

(CDC). The complement component C1q can bind to the crystallizable fragment (Fc) of IgM and IgG bound to cell surface antigens and initiate the classical complement-activation pathway leading to destruction of the target cell.

Phage display

The genetic information of peptides or proteins can be genetically fused to bacteriophage coat protein genes and they are thus individually displayed on phages, thereby linking genotype and phenotype so that the displayed proteins can be screened against defined targets.

Affinity maturation

The production of antibodies with increasing affinity for a target antigen during the course of an adaptive immune response; this process can also be mimicked in vitro.

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Schmid, A.S., Neri, D. Advances in antibody engineering for rheumatic diseases. Nat Rev Rheumatol 15, 197–207 (2019). https://doi.org/10.1038/s41584-019-0188-8

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