Outside in - inside out. Creating focus on the patient - a vaccine company perspective.

Involving patients in the development of medicines and vaccines should result in benefits to patients. The vaccine recipient is usually a healthy person. We describe the rationale and implementation of a vaccine company's initiative to encourage employees to identify with patients of the conditions prevented by the vaccines they help to produce. The Voice of the Patient ("VoP"), begun in 2014, is an educational programme directed at the 16,000 employees of a global vaccine company. It engages employees through an understanding that they are all "vaccine patients", and that they can make a difference by considering the impact of decisions made in their day to day work. The initiative includes presentations about vaccine-preventable diseases, global live webcasts with experts and patients, employee visits to healthcare facilities in developing countries, and the production of patient-focused sections in research publications. In a 2017 employee survey, 90% of respondents said they know how their daily work impacts patients and they demonstrate focus on patients. We believe this is preliminary evidence that, by supporting employee awareness of the impact of their individual roles, VoP could be a model for a type of initiative that will contribute to industry's continuing evolution towards more patient-centred healthcare.

Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the protean effects of "selective" antagonists.

Chemokine receptors constitute an attractive family of drug targets in the frame of inflammatory diseases. However, targeting specific chemokine receptors may be complicated by their ability to form dimers or higher order oligomers. Using a combination of luminescence complementation and bioluminescence resonance energy transfer assays, we demonstrate for the first time the existence of hetero-oligomeric complexes composed of at least three chemokine receptors (CCR2, CCR5, and CXCR4). We show in T cells and monocytes that negative binding cooperativity takes place between the binding pockets of these receptors, demonstrating their functional interaction in leukocytes. We also show that specific antagonists of one receptor (TAK-779 or AMD3100) lead to functional cross-inhibition of the others. Finally, using the air pouch model in mice, we show that the CCR2 and CCR5 antagonist TAK-779 inhibits cell recruitment promoted by the CXCR4 agonist SDF-1 alpha, demonstrating that cross-inhibition by antagonists also occurs in vivo. Thus, antagonists of the therapeutically important chemokine receptors regulate the functional properties of other receptors to which they do not bind directly with important implications for the use of these agents in vivo.

Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers.

Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and human immunodeficiency virus infection. They were shown to dimerize, but the functional relevance of dimerization in terms of drug action remains poorly understood. We reported previously the existence of negative binding cooperativity between the subunits of CCR2/CCR5 heterodimers. In the present study, we extend these observations to heterodimers formed by CCR2 and CXCR4, which are more distantly related. We also show that specific antagonists of one receptor inhibit the binding of chemokines to the other receptor as a consequence of their heterodimerization, both in recombinant cell lines and primary leukocytes. This resulted in a significant functional cross-inhibition in terms of calcium mobilization and chemotaxis. These data demonstrate that chemokine receptor antagonists regulate allosterically the functional properties of receptors on which they do not bind directly, with important implications on the effects of these potential therapeutic agents.