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CHaPTEr 10 Chemokines and Chemokine Receptors 169

tumorigenesis through additional effects on cell growth, angio- gene administration has also been shown to induce neutralizing
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genesis, apoptosis, immune evasion, and metastasis. Controlling antibody against the encoded chemokine, which is able to block
the balance of angiogenic and angiostatic chemokines may be immune responses and to alleviate experimental allergic encepha-
particularly important. Chemokine receptors on tumor cells have lomyelitis and arthritis in rodent models.
been shown to directly mediate chemokine-dependent prolifera- Many chemokines, when delivered pharmacologically as
tion. In Japan, a monoclonal antibody mogamulizumab, which recombinant proteins, by plasmid DNA, or in transfected tumor
blocks CCR4, has been approved for the treatment of adult T-cell cells, are able to induce immunologically mediated antitumor
leukemia or lymphoma, which expresses this receptor at high effects in mouse models and could be clinically useful. Mechanisms
levels. may differ, depending on the model, but may involve recruitment
of monocytes, NK cells, and cytotoxic CD8 T cells to tumor.
THERAPEUTIC APPLICATIONS Chemokines could also be useful as adjuvants in tumor antigen
Chemokines and Chemokine Receptors as Targets for vaccines. Chemokine–tumor antigen fusion proteins represent
a novel variation of this approach, facilitating uptake of tumor
Drug Development antigens by APCs via the normal process of ligand–receptor
Efforts to develop chemokine blocking agents over the past 20 internalization. Non-ELR CXC chemokines, such as CXCL4,
years have so far led to FDA approval of two drugs: maraviroc, also exert antitumor effects through angiostatic mechanisms.
targeting CCR5 as a viral entry factor in HIV/AIDS; and plerixafor, As a final point, the use of chemokine-based immunotoxins to
targeting CXCR4 in HSC mobilization from bone marrow for target disease cell–associated chemokine receptors, including cells
transplantation in cancer patients (see above). 28,33 Chemokine infected with viral chemokine receptors, is quite conceivable.
receptors are the first cytokine receptors for which potent, selective
nonpeptide small molecule antagonists have been identified that CONCLUSION
work in vivo. Targeting host determinants, as in the case of CCR5
in HIV/AIDS, is a new approach in the development of antimi- The chemokine system occupies a central place in immunoregula-
crobial agents. Other candidate disease indications are ACKR1/ tion and is an attractive source of potential drug targets for
Duffy in P. vivax malaria; CXCR4 in WHIM syndrome; CXCR2 any disease with an innate or adaptive immune component. A
in acute neutrophil-mediated inflammation; CXCR3 and CCR2 basic outline of how the system works has been established by
in Th1-driven disease; CCR2 and CX3CR1 in atherosclerosis; using mouse models, and there has been tangible progress in
CCR3 and possibly CCR4 and CCR8 in Th2 diseases, such as the application of this knowledge in clinical practice. Two major
asthma; CCR9 in inflammatory bowel disease; and CCR6 in pioneering successes, CCR5 inhibition in HIV/AIDS and CXCR4
Th17 diseases, such as psoriasis. inhibition for HSC mobilization, have demonstrated the feasibility
Potent and selective nonpeptide small molecule antagonists of of targeting the chemokine system therapeutically in humans.
chemokine receptors, including CXCR2, CXCR3, CXCR4, CCR1, However, both are eccentric indications that address unusual,
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CCR2, CCR3, CCR5, and CCR9 have been reported. These niche roles of chemokine receptors. Satisfactory treatments
molecules share a nitrogen-rich core and appear to block ligand for chronic immune-mediated diseases remain a major unmet
binding by acting at a conserved allosteric site analogous to the medical need, and in this context, the chemokine system offers
retinal-binding site in the transmembrane region of rhodopsin. many drug targets, as well as difficult challenges for the future.
Although small molecules taken as pills are the main goal, other
blocking strategies are also under consideration, such as (1) ACKNOWLEDGMENTS
ribozymes; (2) modified chemokines (e.g., amino-terminally
modified versions of CCL5); (3) intrakines, which are modi- This review was supported with funding from the Division of
fied forms of chemokines delivered by gene therapy that remain Intramural Research, National Institute of Allergy and Infectious
in the endoplasmic reticulum and block surface expression of Diseases, National Institutes of Health (NIH).
newly synthesized receptors; (4) monoclonal antibodies; and (5)
specific gene editing, using the zinc finger nucleases, TALENs Please check your eBook at https://expertconsult.inkling.com/
and CRISPR/Cas9. for self-assessment questions. See inside cover for registration
The fact that viral and tick antichemokines typically block details.
multiple chemokines acting at multiple receptors suggests that
the most clinically effective chemokine-targeted antiinflammatory REFERENCES
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