Around one-third of approved small molecules act on G protein-coupled receptor (GPCR) targets, but these membrane proteins have proved harder to block with antibody-based drugs. With the FDA's August approval of Kyowa Hakko Kirin's mogamulizumab, the US regulators have now set the stage for the second GPCR-targeted antibody to make it to market.
Mogamulizumab acts on CC-chemokine receptor 4 (CCR4), a previously unexploited GPCR target. CCR4 is implicated in cancer, asthma and eczema, and plays a role in controlling the trafficking of immune cells. The surface receptor has stymied the efforts of small-molecule drug developers, but scientists at Kyowa Hakko Kirin found that their mogamulizumab binds to CCR4 on cancer cells, killing them via antibody-dependent cellular cytotoxicity.
The FDA approved the antibody for the treatment of two subtypes of cutaneous T cell lymphoma. In a pivotal trial of 372 patients with these subtypes, patients assigned to mogamulizumab had a median progression-free survival of 7.6 months, compared with 3.1 months for patients assigned to the histone deacetylase inhibitor vorinostat. (Japanese regulators approved the antibody in 2012, based on open-label phase II data.)
Earlier this year, the FDA's approval of Amgen's CGRP inhibitor erenumab for the treatment of migraine marked the first US approval of a GPCR-targeted antibody.
At least ten other GPCR-targeted antibodies are in the clinic, thanks to lucky breaks, scientific advances in structural biology, technological progress in receptor engineering and new antibody-screening strategies (Nat. Rev. Drug Discov. 17, 457–459; 2018).
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Mullard, A. FDA approves second GPCR-targeted antibody. Nat Rev Drug Discov 17, 613 (2018). https://doi.org/10.1038/nrd.2018.153
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DOI: https://doi.org/10.1038/nrd.2018.153