Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology
Source: CD4 T cells (TH2), mast cells.
The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.
Receptors: Type I cytokine receptor family which signals through the Jak-STAT pathway (STAT6). Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.
(click to enlarge the image)
IL-4 effects
- B cells: isotype switching to IgE
- T cells: TH2 differentiation, proliferation
- Macrophages: inhibition of IFN-gamma-mediated activation
- Mast cells: proliferation (in vitro)
IL-4 is the key cytokine for the IgE isotype switch.
Induction of VCAM -1, promotion of eosinophil migration, mucus production.
Th2 lymphocyte differentiation with subsequent release of additional IL-4, IL-5, and IL-13.
IL-4 and GATA3
IL-4 activates STAT6, which then engages the transcription factor GATA3, leading to secretion of IL-4. GATA3 is pivotal for Th2 maturation.
T-bet (also called TBX21 or T-box 21) is pivotal for Th1 maturation. T-bet inhibits IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA3 from interacting with its target DNA. T-bet is a bridge between innate and adaptive immunity (http://buff.ly/1aD6h8s).
Oral synthesis inhibitors of IL-4
Suplatast tosilate inhibits the production of IL-4 and IL-5. In a study of asthmatic patients, there was an improvement in airway hyperresponsiveness, symptoms, and PEFR, and decreased IgE.
Soluble IL-4 receptor
Altrakincept is a recombinant, human IL-4 receptor - the extracellular portion. A small proof-of-concept trials of inhaled altrakincept in asthma showed promise but 2 larger trials failed to confirm efficacy - did not invalidate IL-4 as a target - there were concerns over the bioavailability of altrakincept in those trials.
IL-4Ra receptor antagonist (antibody)
AMG-317 is a fully human mAb antagonist to the IL-4Ra receptor - inhibits both IL-4 and IL-13 signaling). Developed by Amgen (hence the name "AMG") for treatment of allergic asthma.
AMG-317 (AAAAI abstract, March 09): 12-wk RCT, double-blind, 260 subjects with uncontrolled asthma, FEV1 50-80%. Randomized to 12 weekly injections of AMG 317 (75mg, 150mg, 300mg) or placebo. Primary endpoint was improvement in ACQ score.
At week 12, mean improvements in ACQ scores were: placebo (0.48), AMG 317 75mg (0.33), 150mg (0.56), and 300mg (0.65) (p=NS for all). Median improvement in total serum IgE was significantly greater in the 300mg AMG 317 group vs placebo. No AMG 317 treatment-related SAEs were reported.
Aerovant INH and Aeroderm IV
IL-4 mutein that inhibits the effects of both IL-4 and IL-13 through its ability to block IL-4Ra.
Aerovant (Pitrakinra) INH
Aerovant INH: Phase IIa, 30-patient study met its primary endpoint of reducing the severity of late asthmatic response by 72% percent (p lower than 0.001), BID for 27 days. Started in 2009: Phase IIb clinical trial of inhaled dry powder Aerovant in patients with uncontrolled asthma.
http://www.aerovance.com/press_132007.html
http://www.aerovance.com/press_030209.html
Aeroderm IV
PEGylated recombinant human IL-4 variant, block IL-4Ra.
Phase Iia in 24 patients with atopic dermatitis using a non-PEGylated form of the molecule (AER 001). Future studies will be in severe atopic eczema patients using the PEGylated form (AER 003).
http://www.aerovance.com/aeroderm.html
References
Hwang ES; Szabo SJ; Schwartzberg PL; Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 2005 Jan 21;307(5708):430-3.
Tamaoki J, Kondo M, Sakai N, Aoshiba K, Tagaya E, Nakata J, et al. Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Lancet 2000;356:273-8.
Horiguchi T, Tachikawa S, Handa M, Hanazono K, Kondo R, Ishibashi A, et al.Effects of suplatast tosilate on airway inflammation and airway hyperresponsiveness. J Asthma 2001;38:331-6.
Yoshida M, Aizawa H, Inoue H, Matsumoto K, Koto H, Komori M, et al. Effect of suplatast tosilate on airway hyperresponsiveness and inflammation in asthma patients. J Asthma 2002;39:545-52.
Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001;107:963-70
Borish, LC, Nelson, HS, Lanz, MJ, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 1999; 160:1816.
Wenzel, S, Wilbraham, D, Fuller, R, et al. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007; 370:1422.
J. Corren, W. Busse, E. Meltzer3, L. Mansfield4, G. Bensch5, Y. Chon6, M. Dunn6, H. Weng6, S. Lin. Efficacy and Safety of AMG 317, an IL-4Ra Antagonist, in Atopic Asthmatic Subjects: A Randomized, Double-blind, Placebo-controlled Study. JACI, Volume 123, Issue 3, Page 732 (March 2009).
Published: 04/09/2010
Updated: 08/09/2010
IL-4 is the key cytokine for the IgE isotype switch.
Induction of VCAM -1, promotion of eosinophil migration, mucus production.
Th2 lymphocyte differentiation with subsequent release of additional IL-4, IL-5, and IL-13.
IL-4 and GATA3
IL-4 activates STAT6, which then engages the transcription factor GATA3, leading to secretion of IL-4. GATA3 is pivotal for Th2 maturation.
T-bet (also called TBX21 or T-box 21) is pivotal for Th1 maturation. T-bet inhibits IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA3 from interacting with its target DNA. T-bet is a bridge between innate and adaptive immunity (http://buff.ly/1aD6h8s).
Oral synthesis inhibitors of IL-4
Suplatast tosilate inhibits the production of IL-4 and IL-5. In a study of asthmatic patients, there was an improvement in airway hyperresponsiveness, symptoms, and PEFR, and decreased IgE.
Soluble IL-4 receptor
Altrakincept is a recombinant, human IL-4 receptor - the extracellular portion. A small proof-of-concept trials of inhaled altrakincept in asthma showed promise but 2 larger trials failed to confirm efficacy - did not invalidate IL-4 as a target - there were concerns over the bioavailability of altrakincept in those trials.
IL-4Ra receptor antagonist (antibody)
AMG-317 is a fully human mAb antagonist to the IL-4Ra receptor - inhibits both IL-4 and IL-13 signaling). Developed by Amgen (hence the name "AMG") for treatment of allergic asthma.
AMG-317 (AAAAI abstract, March 09): 12-wk RCT, double-blind, 260 subjects with uncontrolled asthma, FEV1 50-80%. Randomized to 12 weekly injections of AMG 317 (75mg, 150mg, 300mg) or placebo. Primary endpoint was improvement in ACQ score.
At week 12, mean improvements in ACQ scores were: placebo (0.48), AMG 317 75mg (0.33), 150mg (0.56), and 300mg (0.65) (p=NS for all). Median improvement in total serum IgE was significantly greater in the 300mg AMG 317 group vs placebo. No AMG 317 treatment-related SAEs were reported.
Aerovant INH and Aeroderm IV
IL-4 mutein that inhibits the effects of both IL-4 and IL-13 through its ability to block IL-4Ra.
Aerovant (Pitrakinra) INH
Aerovant INH: Phase IIa, 30-patient study met its primary endpoint of reducing the severity of late asthmatic response by 72% percent (p lower than 0.001), BID for 27 days. Started in 2009: Phase IIb clinical trial of inhaled dry powder Aerovant in patients with uncontrolled asthma.
http://www.aerovance.com/press_132007.html
http://www.aerovance.com/press_030209.html
Aeroderm IV
PEGylated recombinant human IL-4 variant, block IL-4Ra.
Phase Iia in 24 patients with atopic dermatitis using a non-PEGylated form of the molecule (AER 001). Future studies will be in severe atopic eczema patients using the PEGylated form (AER 003).
http://www.aerovance.com/aeroderm.html
References
Hwang ES; Szabo SJ; Schwartzberg PL; Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 2005 Jan 21;307(5708):430-3.
Tamaoki J, Kondo M, Sakai N, Aoshiba K, Tagaya E, Nakata J, et al. Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Lancet 2000;356:273-8.
Horiguchi T, Tachikawa S, Handa M, Hanazono K, Kondo R, Ishibashi A, et al.Effects of suplatast tosilate on airway inflammation and airway hyperresponsiveness. J Asthma 2001;38:331-6.
Yoshida M, Aizawa H, Inoue H, Matsumoto K, Koto H, Komori M, et al. Effect of suplatast tosilate on airway hyperresponsiveness and inflammation in asthma patients. J Asthma 2002;39:545-52.
Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001;107:963-70
Borish, LC, Nelson, HS, Lanz, MJ, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 1999; 160:1816.
Wenzel, S, Wilbraham, D, Fuller, R, et al. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007; 370:1422.
J. Corren, W. Busse, E. Meltzer3, L. Mansfield4, G. Bensch5, Y. Chon6, M. Dunn6, H. Weng6, S. Lin. Efficacy and Safety of AMG 317, an IL-4Ra Antagonist, in Atopic Asthmatic Subjects: A Randomized, Double-blind, Placebo-controlled Study. JACI, Volume 123, Issue 3, Page 732 (March 2009).
Published: 04/09/2010
Updated: 08/09/2010
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