Table 1 Examples of Targeted Therapies in Preclinical or Clinical Development in Severe Asthma
Strategy | Target | Drug | Biological or Clinical Effects | References |
|---|---|---|---|---|
Cell surface protein | Siglec-8 | Anti-Siglec 8 monoclonal antibody | Apoptosis of eosinophils | Nutku et al., Blood 101: 5014, 2003 [107] Bochner et al., Clin. Exp. Allergy 39: 317, 2009 [108] |
CD172a | Inhibitor of signaling | Verjan Garcia et al., J. Immunol. 187: 2288, 2011 [109] | ||
CD300a | Activation of inhibitory receptor | Munitz et al., Blood 107: 1996, 2006 [110] | ||
Immunoglobulin-like receptor B | Munitz et al., Blood 111: 5694, 2008 [111] | |||
α4β1, α4β7 | Natalizumab | Increase blood eosinophils and inhibits their tissue accumulation | Abbas et al., Neurology 77: 1561, 2011 [112] | |
α4β7 integrin | Vedolizumab | No effect | Soler et al., JPET 330: 864, 2009 [113] | |
α4β7 , αEβ7 | Etrolizumab | Unknown | ||
CCR3 | GW766944 | Block chemokine-induced eosinophils in vitro; no effect in vivo | Neighbour et al., Clin. Exp. Allergy 44: 508, 2014 [114] | |
CXCR2 | SCH527123 | Reduce blood and sputum neutrophils | Nair et al., Clin. Exp. Allergy 42: 1097, 2012 [115] | |
CD52 | Alemtuzumab | Deplete eosinophils in vivo | Wechsler et al., JACI 130: 563, 2012 [116] | |
CD131 | CSL311 | Unknown | ||
CRTH2 | 0C000459 | Reduce tissue eosinophils | Pettipher et al., Allergy 69: 1223, 2014 [117] | |
ACT-453859 | CRTH2 blockade | Géhin et al., J. Clin. Pharmacol. 55: 787, 2015 [118] | ||
EMR1 | Afucosylated anti-EMR1 monoclonal antibody | Deplete primate eosinophils | Legrand et al., JACI 133: 1439, 2014 [119] | |
Interleukin-4Rα | Dupilumab | Reduce airway eosinophils | NCT01312961 | |
Interleukin-4Rα | AMG-317 | Do not reduce airway eosinophils | Corren et al., Am. J. Resp. Crit. Care Med. 181: 788, 2010 [120] | |
H4 Receptor | UR-63325 JNJ 28610244 | Salcedo et al., Front Biosci 5: 178, 2013 [121] Dib et al., JLB 96: 411, 2014 [122] | ||
Soluble mediator antagonist | Eotaxin-1 | Bertilimumab | Inhibit Eotaxin-1 mediated eosinophil activation in vitro | Ding et al., Curr. Opin. Investig. Drug 5: 1213, 2004 [123] |
IgE | Omalizumab | Reduces eosinophils at sites of allergic inflammation and peripheral blood | Detoraki et al., J. Asthma 53: 201, 2016 [44] | |
IL-4 | Altrakincept Pascolizumab Pitrakinra | Reduce eosinophils at sites of allergic inflammation | Borish et al., Am. J. Resp. Crit. Care Med. 160: 1816, 1999 [124] Hart et al., Clin. Exp. Immunol. 130: 93, 2002 [125] | |
IL-13 | Tralokinumab Lebrikizumab Anrukinzumab RPC4046 QAX576 | Reduce eosinophils in blood and at sites of allergic inflammation | Blanchard et al., Clin. Exp. Allergy 35: 1096, 2005 [126] Maselli et al., J. Asthma Allergy 8: 87, 2015 [127] | |
Interleukin-17RA | Brodalumab | No effect | Busse et al., Am J Respir Crit Care Med 188: 1294, 2013 [35] | |
TSLP | AMG157 | Reduce eosinophils in blood and at sites of allergic inflammation | Gauvreau et al., NEJM 370: 2102, 2014 [57] | |
Transcription factor | GATA3 | SB010 | Reduce IL-5 and late asthmatic response after allergen challenge | Krug et al., NEJM 372: 1987, 2015 [42] |