Potent Antiviral Synergy between Monoclonal Antibody and Small-Molecule CCR5 Inhibitors of Human Immunodeficiency Virus Type 1

Progenics Pharmaceuticals, Inc, Tarrytown, NY 10591, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 11/2006; 50(10):3289-96. DOI: 10.1128/AAC.00699-06
Source: PubMed


The chemokine receptor CCR5 provides a portal of entry for human immunodeficiency virus type 1 (HIV-1) into susceptible CD4(+) cells. Both monoclonal antibody (MAb) and small-molecule CCR5 inhibitors have entered human clinical testing, but little is known regarding their potential interactions. We evaluated the interactions between CCR5 MAbs, small-molecule CCR5 antagonists, and inhibitors of HIV-1 gp120, gp41, and reverse transcriptase in vitro. Inhibition data were analyzed for cooperative effects using the combination index (CI) method and stringent statistical criteria. Potent, statistically significant antiviral synergy was observed between the CCR5 MAb PRO 140 and the small-molecule CCR5 antagonists maraviroc (UK-427,857), vicriviroc (SCH-D), and TAK-779. High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels. CI values ranged from 0.18 to 0.64 and translated into in vitro dose reductions of up to 14-fold. Competition binding studies revealed nonreciprocal patterns of CCR5 binding by MAb and small-molecule CCR5 inhibitors, suggesting that synergy occurs at the level of receptor binding. In addition, both PRO 140 and maraviroc synergized with the chemokine RANTES, a natural ligand for CCR5; however, additive effects were observed for both small-molecule CCR5 antagonists and PRO 140 in combination with other classes of HIV-1 inhibitors. The findings provide a rationale for clinical exploration of MAb and small-molecule CCR5 inhibitors in novel dual-CCR5 regimens for HIV-1 therapy.

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    • "Alanine scanning indicated that PRO-140 recognizes a conformational epitope spanning the N-terminus, extracellular loops 1 and 2 on CCR5. When used in combination with Maraviroc, Vicriviroc and TAK-779, synergistic drug effect was observed as compared to additive effects when combined with reverse transcriptase inhibitors (Murga et al., 2006). In a phase 1b study, a substantially enhanced mean reduction of viral load was observed in 2 mg/kg and 5 mg/kg groups of PRO-140 as compared with the placebo control. "
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    • "The other anti-CCR5 mAb is PRO 140, a humanized mAb that also synergizes with small-molecule CCR5 antagonists in laboratory studies [95]. PRO140 is being investigated in two modes of administration: the classical intravenous (IV) form, and subcutaneous (SC) form. "
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    • "A related but simpler case is the strong synergy observed here and previously between a MAb and a small molecule that both bind to CCR5 (Ji et al., 2007; Latinovic et al., 2011a; Murga et al., 2006). Although the small CCR5 ligand may enhance the binding of the MAb (Latinovic et al., 2011b), the binding of the two ligands can also be antagonistic (Murga et al., 2006). Furthermore, the MAb and the small molecule can be active in different (Safarian et al., 2006) or the same (Ji et al., 2007) time windows and still synergize. "
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