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Next generation antibody drugs: pursuit of the 'high-hanging fruit'

Key Points

  • Antibodies are the fastest growing drug class, with >60 antibody drugs approved and >550 more in clinical development.

  • Many of the most tractable and best understood cell surface and secreted targets with known roles in human diseases have been extensively exploited for antibody drug development.

  • New opportunities for antibody drugs may be possible by developing antibodies with novel mechanisms of action, such as those that induce tumour cell killing or receptor agonism.

  • Additional opportunities for antibody drugs are anticipated by overcoming existing obstacles to delivery, such as poorly accessible sites of action including the brain, lungs and gastrointestinal tract and perhaps ultimately the cytosol of cells.

  • Bispecific and multispecific targeting with antibodies is enabling advances in immune cell recruitment, improvements in tissue selectivity and novel mechanistic approaches to agonism and transport.

  • Targets that are currently not amenable to antibody approaches — the 'high-hanging fruit' — may become druggable in the future through continued innovation.

Abstract

Antibodies are the most rapidly growing drug class and have a major impact on human health, particularly in oncology, autoimmunity and chronic inflammatory diseases. Many of the best understood and most tractable cell surface and secreted targets with known roles in human diseases have been extensively exploited for antibody drug development. In this Review, we focus on emerging and novel mechanisms of action of antibodies and innovative targeting strategies that could extend their therapeutic applications, including antibody–drug conjugates, bispecific antibodies and antibody engineering to facilitate more effective delivery. These strategies could enable the pursuit of difficult to hit, less well-understood or previously undruggable targets — the 'high-hanging fruit'.

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Figure 1: Formats of approved antibody drugs.
Figure 2: Fruit tree model to represent the difficulty of antibody drug development for different therapeutic targets.
Figure 3: Direct and indirect targeting of tumours with marketed antibody drugs.

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Acknowledgements

The authors thank J. Reichert (Antibody Society) for contributing data for TABLE 1 and for helpful discussions. They also thank their Genentech colleagues J. Atwal, R. Brezski, H. Erickson, J. Koerber, M. van Lookeren Campagne, L. Sun and C. Spiess for crucial review of this manuscript plus J. Melvin and B. Lassoff for compiling the commercial data in TABLE 1. The authors thank anonymous peer reviewers for their insightful feedback and apologize to researchers whose work they were unable to cite owing to space limitations.

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Correspondence to Paul J. Carter or Greg A. Lazar.

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The authors are employees of Genentech, a member of the Roche Group that develops and commercializes therapeutics including antibody-based drugs.

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Glossary

Biosimilar antibodies

Antibodies produced using different clones and cell lines than the original approved antibody product of identical amino acid sequence, often by a different manufacturer.

Blockbuster

A term used for pharmaceuticals to refer to those drugs with annual sales of at least US$1 billion per year.

Mechanisms of action

(MoAs). Specific biochemical interactions and biological processes through which a drug elicits its pharmacologic effects.

Effector functions

Fc-mediated antibody properties that allow for target cell depletion via immune mechanisms including antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell-mediated phagocytosis and complement-dependent cytotoxicity.

Epitope

The part of an antigen that is contacted by an antibody.

Plasma half-life

The time taken for the plasma concentration of a drug to decrease to half of its original value. The initial half-life and terminal half-life refer to the distribution phase and elimination phase of biexponential pharmacokinetics, respectively.

Adverse events

Undesirable experiences associated with the use of a medical product in a patient that do not necessarily have a causal relationship with that product.

Therapeutic index

A ratio of drug doses that cause toxic versus therapeutic effects that is used to assess the relative safety of the drug for a particular treatment

Biparatropic antibody

An antibody that binds to two different sites (epitopes) on the same antigen via two different sites (paratopes) on the antibody; also called a biepitopic antibody.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). The killing of an antibody-coated target cell by a cytotoxic effector cell through a lytic process typically involving the release of cytotoxic granules.

Antibody-dependent cell-mediated phagocytosis

(ADCP). The engulfment of an antibody-coated target cell by a phagocytic effector cell.

Complement-dependent cytotoxicity

(CDC). The killing of an antibody-coated target cell via recruitment of the complement membrane attack complex (C5b–9).

Anti-drug antibodies

(ADAs). Antibodies that can result from an immune response to the therapeutic administration of an antibody or other protein drug.

Volume of distribution

The theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration as observed in the blood plasma.

Interstitial fluid

Fluid that bathes and surrounds tissues.

Cerebrospinal fluid

Clear and colourless fluid found in the brain and spine.

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Carter, P., Lazar, G. Next generation antibody drugs: pursuit of the 'high-hanging fruit'. Nat Rev Drug Discov 17, 197–223 (2018). https://doi.org/10.1038/nrd.2017.227

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