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Therapeutic targeting of EPH receptors and their ligands

Key Points

  • EPH receptors (EPHs), together with cell-bound signalling-competent ligands (ephrins), regulate cell positioning, tissue patterning and stem cell maintenance during normal and neoplastic development.

  • Their specialized functions are driven via the signalling of oligomeric EPH–ephrin clusters into both interacting cells, whereby the diversity of possible EPH–ephrin interactions and crosstalk with major signalling pathways generate a spectrum of signalling outcomes.

  • Their crucial roles in cancer, in neural remodelling after brain and central nervous system injuries, in pathological vascular and bone remodelling and in stem cell niche maintenance have sparked growing interest in exploring EPHs and ephrins as therapeutic targets.

  • Targeted therapeutics, including antibodies, soluble EPH or ephrin fusion proteins, drug conjugates and small-molecule inhibitors are being developed to inhibit EPH and ephrin binding, activation, biosynthesis and downstream signalling.

  • In cancer, EPHs have context- and tumour stage-dependent functions as tumour suppressors or tumour promotors: targeting with agonistic or antagonistic antibodies, soluble EPH (ephrin) fusion proteins, drug conjugates and kinase inhibitors has shown therapeutic effects in the tumour microenvironment as well as in tumour and tumour stem cell compartments.

  • In traumatic brain and spinal cord injuries, overexpression of EPHA4, among other EPHs, inhibits neuronal regrowth; and inhibition with soluble EPH or ephrin–Fc fusion proteins or peptides is being developed for therapeutic use.

  • Although EPHs and ephrins are also implicated in a range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis and motor neuron disease, as well as in inflammatory diseases, strategies for their therapeutic targeting in these areas are only emerging.

  • Greatest advances with the development of EPH-targeted therapeutics have been achieved in oncology, where early clinical trials show promise with antibody therapeutics in leukemias and with broad-spectrum tyrosine kinase inhibitors in non-small-cell lung cancer.

Abstract

Critical roles for EPH receptor (EPH)–ephrin signalling in a range of chronic and regenerative diseases are increasingly being recognized. In particular, the complex roles of EPHs and ephrins in tumour growth and progression, and in nerve injury and regeneration have been studied extensively. This has led to considerable progress in developing strategies for their therapeutic targeting, with some anticancer agents already in clinical trials. Promising leads for non-malignant diseases are also emerging, with compelling preclinical data encouraging clinical development. We discuss this rapidly developing area of drug discovery, highlighting the associated challenges and limitations.

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Figure 1: EPH structure and signalling concepts.
Figure 2: EPH and ephrin B crosstalk with cell signalling pathways.
Figure 3: Strategies for therapeutic targeting of EPH and ephrin functions.

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Acknowledgements

We respectfully dedicate this Review to the memory of Tony Pawson, a pioneering discoverer of tyrosine kinase function and a founder of the EPH kinase field.

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Correspondence to Martin Lackmann.

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M.L. and A.B. hold patents that have been licensed to KaloBios, and research in their laboratories is supported in part by funding from KaloBios Pharmaceuticals.

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Glossary

Ephrins

EPH receptor interacting proteins.

Tissue patterning

A self-organizing principle during development that allows the generation of defined groups of cells, which are spatially segregated from (groups of) phenotypically distinct cells; such segregation gives tissues their characteristic morphology. Patterning relies on interplay between cell-intrinsic activity of the actin–myosin network and the modulation of cell–cell adhesion mechanisms.

Glycosyl phosphatidylinositol

(GPI). A glycosylated lipid anchor that links various proteins at their free carboxyl end to a terminal mannose unit of the GPI moiety. GPI-anchored proteins account for approximately 20% of membrane proteins, including the A-type ephrins, which partition to specific sphingolipid- and cholesterol-enriched membrane domains.

Synaptic plasticity

The ability of synapses (the cellular junctions between pre-and postsynaptic neurons) to change in strength and thereby to modulate signal flow. Whereas intrinsic plasticity is due to changes in the signal transmitting capacity of synaptic receptors, extrinsic plasticity is due to synaptic interaction with a regulatory cell. The regulatory cell modulates the ability of the presynaptic cell to release transmitter (signal) into the postsynaptic cell.

Fusion proteins

(Also known as chimeric proteins). Recombinant proteins that are composed of two unrelated, functionally intact components.

Cis interactions

Cell surface receptors (such as EPH receptors) that bind to cell-bound ligands (such as ephrins) on neighbouring cells communicate in trans. If these receptors can also interact with ligands that are expressed on the same cell surface, this is defined as a cis interaction. The biological consequences of the cis and trans interactions are often different if not contrary to each other.

Kinase-independent signalling

Canonical signalling by receptor tyrosine kinases occurs with tyrosine phosphorylation of their cytoplasmic residues as an initiating event that triggers downstream signalling cascades. However, receptor tyrosine kinases, such as EPH receptors, contain additional protein interaction domains, such as PDZ binding motifs, which initiate distinct signalling pathways in the absence of kinase activity.

Axon pathfinding

A cell-intrinsic mechanism of nerve cells that allows them to navigate by extending their growth cones over long distances to find the correct destination within the body. This 'axon guidance' is facilitated by molecular cues provided via cell surface proteins such as EPH receptors and ephrins, which guide the direction of extending growth cones by exerting cell contact-dependent adhesive or repulsive forces.

PDZ

A structural protein domain that binds to the carboxy-terminal consensus sequence Gly-Leu-Gly-Phe, which is present in a range of transmembrane receptors and facilitates the formation of protein signalling complexes. The name stems from the first three proteins identified to contain a PDZ domain: post-synaptic density protein 95 (PSD95), disc large tumour suppressor 1 (DLG1) and zonula occludens 1 (ZO1).

Dendritic spine morphogenesis

The process in which the anatomical structures of a dendritic spine are generated and organized. The process involves bidirectional signalling of surface receptors, such as EPH receptors, RHO GTPases, scaffold proteins and actin-binding proteins. Dendritic spines are small protrusions from the dendrites of most principal mammalian brain neurons, and they contain all of the essential molecules and organelles that are involved in postsynaptic signalling and plasticity.

Long-term potentiation

(LTP). The long lasting strengthening of signal transmission between presynaptic and postsynaptic neurons that results from their synchronous stimulation. LTP is one of several concepts underlying synaptic plasticity, which is considered to be the cellular basis for memory and learning.

Sprouting angiogenesis

One of the processes in which new blood vessels develop from pre-existing vessels. It involves specification of endothelial cells into morphologically, phenotypically and functionally distinct migratory cells at the tip of the new vessel sprout and into proliferating stalk cells that form the nascent vascular lumen of the emerging vessel. The phenotypic specialization of endothelial cells as tip or stalk cells is transient and reversible and depends on the balance between pro-angiogenic factors, including vascular endothelial growth factor, Notch and EPH receptors.

Stem cell niches

The tissue or organ microenvironments that support the establishment and maintenance of stem cell populations and regulate their involvement in tissue generation, maintenance and repair. A range of factors in the stem cell niche tightly controls a fine balance between stem cell proliferation and differentiation.

Agonistic monoclonal antibodies

(Agonistic mAbs). Antibodies that enhance the function of an antigen of interest by recognizing and binding to a single specific epitope of the antigen (hence 'monoclonal'). In the case of a receptor tyrosine kinase, binding of an agonistic antibody triggers tyrosine kinase activation and signalling.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A mechanism of cell-mediated innate immunity in which Fc receptor-mediated binding of immune effector cells (such as macrophages and natural killer cells) to antibody-opsonized target cells (such as foreign cells or cancer cells) leads to effector cell activation, cytokine release and target cell killing.

Ephrin B2–Fc

A chimeric protein composed of ephrin B2 extracellular domains fused to the Fc portion of human immunoglobulin. Fusing EPH receptors (EPHs) or ephrins with Fc produces an antibody-like fusion protein in which both of the antibody Fab fragments are replaced by the EPH or ephrin extracellular domains.

Traumatic brain injury

(TBI). Single or repeated impacts to the head that result in immediate post-traumatic sensory, motor and neurocognitive syndromes due to brain contusions, intracerebral haemorrhage and axonal shearing, as well as progressive neurological dysfunction after repetitive insult.

Spinal cord injury

(SCI). A partial or complete injury to the spinal cord that is often caused by fracture or dislocation of the vertebrae, leading to tearing or complete severing of the nerve fibres of the spinal cord.

Demyelinating disease

A condition that results in damage to the protective myelin sheath surrounding nerve fibres in brain and spinal cord. This damage to the myelin sheath results in significant slowing or stopping of signal transmitting capacity, in turn causing deficiency in sensation, movement or cognition.

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Boyd, A., Bartlett, P. & Lackmann, M. Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov 13, 39–62 (2014). https://doi.org/10.1038/nrd4175

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