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  • Review Article
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The promise and challenges of immune agonist antibody development in cancer

Abstract

Immune cell functions are regulated by co-inhibitory and co-stimulatory receptors. The first two generations of cancer immunotherapy agents consist primarily of antagonist antibodies that block negative immune checkpoints, such as programmed cell death protein 1 (PD1) and cytotoxic T lymphocyte protein 4 (CTLA4). Looking ahead, there is substantial promise in targeting co-stimulatory receptors with agonist antibodies, and a growing number of these agents are making their way through various stages of development. This Review discusses the key considerations and potential pitfalls of immune agonist antibody design and development, their differentiating features from antagonist antibodies and the landscape of agonist antibodies in clinical development for cancer treatment.

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Figure 1: The B7–CD28 and TNFR families of co-stimulatory receptors.
Figure 2: Mechanisms of receptor supercluster formation with co-stimulatory agonists.
Figure 3: Optimal stoichiometry for receptor supercluster formation.
Figure 4: Model for potential dual activities of some immune agonist antibodies.
Figure 5: Hexavalent TNFR agonist.

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All authors researched the data for article, provided substantial contribution to discussion of content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Axel Hoos.

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A.H. and K.W.H. are employees and shareholders of GlaxoSmithKline. P.A.M. is an employee and shareholder of Incyte Corporation.

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Glossary

Valency

The number of antigen binding sites that an individual antibody can engage.

Fcγ receptors

(FcγRs). Receptors expressed on the surface of cells that can bind specifically to the crystallizable fragment (Fc) region of an antibody.

Immune synapse

The interface between an antigen-presenting cell (such as a dendritic cell) and a T cell or natural killer cell.

Receptor supercluster

A large grouping of receptors on the cell membrane typically occurring in lipid rafts or the immune synapse.

Affinity-matured

Outcome of the in vitro process to improve the binding affinity of an antibody for an antigen through successive rounds of complementarity-determining region mutagenesis and clonal selection.

Protein A crosslink

The simultaneous binding of multiple immunoglobulin G (IgG) molecules by a single protein A molecule, leading to IgG clustering or crosslinking.

Receptor crosslinking

The active process of receptor clustering that occurs when bivalent antigen-binding fragment (Fab) domains of a single antibody bind to multiple receptors; the process can be mediated by the interaction of the crystallizable fragment (Fc) domain with Fcγ receptors.

Sigmoidal dose–response

A dose–response relationship in which the logarithm of the drug concentration plotted on the x axis results in an activity–response curve with a sigmoidal shape, wherein drug activity increases exponentially at the middle concentrations and plateaus at high concentrations.

Bell-shaped dose–response

A dose–response relationship in which the logarithm of the drug concentration plotted on the x axis results in an activity–response curve with a bell or umbrella shape, wherein drug activity is maximal at middle concentrations and decreases as concentration increases further.

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Mayes, P., Hance, K. & Hoos, A. The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov 17, 509–527 (2018). https://doi.org/10.1038/nrd.2018.75

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