Upload
lamthuan
View
217
Download
0
Embed Size (px)
Citation preview
Monoclonal Monoclonal
Antibodies in Asthma Antibodies in Asthma
TherapyTherapy
Yehia ElYehia El--Gamal Gamal
MD, PhDMD, PhD
ObjectivesObjectives
Following this presentation, the Following this presentation, the
audience should be able to:audience should be able to:
••Recognize some important monoclonal Recognize some important monoclonal
antibodies available for asthma therapy.antibodies available for asthma therapy.
••Identify candidates for treatment with Identify candidates for treatment with
monoclonal antibodies.monoclonal antibodies.
••Be aware of the side effects and costBe aware of the side effects and cost--
benefit of such therapy. benefit of such therapy.
Since the first Since the first
publication by Kohler publication by Kohler
and Milstein on the and Milstein on the
production of murine production of murine
monoclonal antibodies monoclonal antibodies
(MAbs) by hybridoma (MAbs) by hybridoma
technology, therapeutic technology, therapeutic
use of MAbs has use of MAbs has
become a major part of become a major part of
treatments in various treatments in various
diseases. diseases. KKööhler G, Milstein C. Nature 1975;256: hler G, Milstein C. Nature 1975;256:
495495--7.7.
http://en.wikipedia.org/wiki/Monhttp://en.wikipedia.org/wiki/Mon
oclonal_antibodiesoclonal_antibodies
Schematic representation of MAb productionSchematic representation of MAb production
MartinMartin--Mateos MA. Allergol Immunopathol (Madr) 2007; 35(4):145Mateos MA. Allergol Immunopathol (Madr) 2007; 35(4):145--50.50.
OmalizumabOmalizumab (anti(anti--IgE ab) IgE ab)
•• It is a recombinant humanized It is a recombinant humanized monoclonal antibody (rhuMAbmonoclonal antibody (rhuMAb--E25) E25) developed by immunizing mice with developed by immunizing mice with human IgE. human IgE.
•• Then, a monoclonal antibody was Then, a monoclonal antibody was selected that recognizes IgE at the selected that recognizes IgE at the same site as the highsame site as the high--affinity receptor affinity receptor for IgE (Fcfor IgE (FcεεRI).RI).
Milgrom H, et al. N Engl J Med 1999;341(26):1966Milgrom H, et al. N Engl J Med 1999;341(26):1966--73.73.
MAbs in allergic diseases (contMAbs in allergic diseases (cont’’d)d)
MAbs in allergic diseases (contMAbs in allergic diseases (cont’’d)d)
OmalizumabOmalizumab is the only MAb to is the only MAb to
date that has been found to be date that has been found to be
effective and approved by both effective and approved by both
the FDA and European the FDA and European
Medicines Agency (EMEA) for Medicines Agency (EMEA) for
the treatment of difficult allergic the treatment of difficult allergic
asthma. asthma. Bousquet J, et al. Expert Opin Biol Ther 2008;8(12):1921Bousquet J, et al. Expert Opin Biol Ther 2008;8(12):1921--8.8.
Mechanisms of Action of OmalizumabMechanisms of Action of Omalizumab
•• Reduces serum levels of free IgE Reduces serum levels of free IgE
•• DownDown--regulates expression of IgE regulates expression of IgE
receptors (FceRI) on mast cells and receptors (FceRI) on mast cells and
basophils. basophils.
•• In the airways of patients with allergic In the airways of patients with allergic
asthma, it reduces Fcasthma, it reduces FcεεRI+ and IgE+ cells RI+ and IgE+ cells
and causes a profound reduction in tissue and causes a profound reduction in tissue
eosinophilia, together with reductions in eosinophilia, together with reductions in
submucosal Tsubmucosal T--cell and Bcell and B--cell numbers.cell numbers.
Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. Holgate S, Casale T, Wenzel S, Bousquet J, Deniz Y, Reisner C. J J
Allergy Clin Immunol 2005;115(3):459Allergy Clin Immunol 2005;115(3):459--65. 65.
Mechanisms of action of omalizumab (contMechanisms of action of omalizumab (cont’’d)d)
•• The reductions in circulating levels of IgE The reductions in circulating levels of IgE
resulting from omalizumab treatment leads to resulting from omalizumab treatment leads to
reductions in FceRI expression on mast cells, reductions in FceRI expression on mast cells,
basophils and dendritic cells. basophils and dendritic cells.
•• This combined effect results in attenuation of This combined effect results in attenuation of
several markers of inflammation, including several markers of inflammation, including
peripheral and bronchial tissue eosinophilia, peripheral and bronchial tissue eosinophilia,
levels of GMlevels of GM--CSF, ILCSF, IL--2, IL2, IL--4, IL4, IL--5 and IL5 and IL--13. 13.
•• It may also reduce allergen presentation to TIt may also reduce allergen presentation to T--
cells and the production of Th2 cytokines.cells and the production of Th2 cytokines.
Holgate S, et al. Allergy 2009:64(12):1728Holgate S, et al. Allergy 2009:64(12):1728––36.36.
Fig 2
Source: Journal of Allergy and ClinOI:10.1016/j.jaci.2004.11.053 )
Proposed Mechanisms of Action of OmalizumabProposed Mechanisms of Action of Omalizumab
Holgate S, et al. J Allergy Clin Immunol 2005;115(3):459Holgate S, et al. J Allergy Clin Immunol 2005;115(3):459--65. 65.
Treatment of allergic asthma with Treatment of allergic asthma with
monoclonal antimonoclonal anti--IgE antibody: IgE antibody:
rhuMAbrhuMAb--E25 Study Group.E25 Study Group.
Serum concentrations of total and free IgE in subjects given a Serum concentrations of total and free IgE in subjects given a
low dose of rhuMAblow dose of rhuMAb--E25 for 20 weeksE25 for 20 weeks
Milgrom H, et al. N Engl J Med. 1999 Dec 23;341(26):1966Milgrom H, et al. N Engl J Med. 1999 Dec 23;341(26):1966--73.73.
Fig 1
Immunohistochemical Immunohistochemical
staining of bronchial biopsy staining of bronchial biopsy
specimens before (specimens before (leftleft) and ) and
after (after (rightright) 16 weeks of ) 16 weeks of
omalizumab treatment. omalizumab treatment.
Representative sections Representative sections
show staining with show staining with
antibody against: antibody against:
ECP ECP (A and B)(A and B)
CellCell--surface IgE surface IgE (C and D) (C and D)
HighHigh--affinity IgE R affinity IgE R (E and F) (E and F)
ILIL--4 4 (G and H)(G and H)
DjukanoviDjukanovićć R, et al. Am J Respir Crit R, et al. Am J Respir Crit
Care Med 2004;170:583Care Med 2004;170:583--93.93.
Fig 1
Eosinophil apoptosis Eosinophil apoptosis
at baseline and week at baseline and week
12 of omalizumab 12 of omalizumab
therapy: therapy:
The omalizumab The omalizumab
group (n = 9) group (n = 9)
demonstrated a demonstrated a
significant increase in significant increase in
AnnexinAnnexin--positive positive
eosinophils compared eosinophils compared
with placebo (n = 10). with placebo (n = 10).
∗∗∗∗∗∗∗∗∗∗∗∗∗∗∗∗ p < 0.01p < 0.01
Noga O,et al. Noga O,et al. J Allergy Clin Immunol 2006;117:1493J Allergy Clin Immunol 2006;117:1493––9.9.
Individual eosinophil counts at baseline and after 12 weeks of Individual eosinophil counts at baseline and after 12 weeks of
treatment with omalizumab or placebo. Horizontal bars represent treatment with omalizumab or placebo. Horizontal bars represent
median valuesmedian values
van Rensen E, van Rensen E, et al. et al. Allergy 2009;64:72Allergy 2009;64:72––80.80.
van Rensen E, van Rensen E, et al. et al. Allergy 2009;64:72Allergy 2009;64:72––80.80.
Forced Forced
expiratory expiratory
volume in 1 volume in 1
second as a second as a
percentage of percentage of
baseline in the baseline in the
placebo (A) and placebo (A) and
omalizumab (B) omalizumab (B)
groups.groups.
Effect of addEffect of add--on therapy with omalizumab in on therapy with omalizumab in
patients with severe persistent asthma whose patients with severe persistent asthma whose
asthma was inadequately controlled by therapy with asthma was inadequately controlled by therapy with
highhigh--dose ICSs plus a LABAdose ICSs plus a LABA
Humbert M, et al. Allergy 2005; 60:309Humbert M, et al. Allergy 2005; 60:309––1616
AntiAnti--IgE Therapy in ChildrenIgE Therapy in Children
•• Omalizumab is approved for the treatment of Omalizumab is approved for the treatment of
adults and adolescents (12 years) with adults and adolescents (12 years) with
inadequately controlled moderateinadequately controlled moderate--toto--severe severe
(United States) or severe (Europe) allergic (IgE(United States) or severe (Europe) allergic (IgE--
mediated) asthma.mediated) asthma.
http://www.xolair.com/prescribing_information.html. http://www.xolair.com/prescribing_information.html.
http://www.emea.europa.eu/humandocs/Humans/EPAR/xolair/xolair.hthttp://www.emea.europa.eu/humandocs/Humans/EPAR/xolair/xolair.htm. m.
•• A randomized DBPC study in 334 children (6 to 12 A randomized DBPC study in 334 children (6 to 12
years) with moderateyears) with moderate--toto--severe allergic asthma, severe allergic asthma,
omalizumab significantly reduced asthma omalizumab significantly reduced asthma
exacerbations and enabled reductions in ICS dose.exacerbations and enabled reductions in ICS dose.
Milgrom H, et al. Pediatrics 2001;108:E36.Milgrom H, et al. Pediatrics 2001;108:E36.
AntiAnti--IgE Therapy in Children (contIgE Therapy in Children (cont’’d)d)
More recently, Lanier et al. More recently, Lanier et al.
demonstrated, in a RDBPC trial, that demonstrated, in a RDBPC trial, that
addadd--on therapy with omalizumabon therapy with omalizumab has a has a
reassuring safety profile, with no reassuring safety profile, with no
increased risk of adverse events, and increased risk of adverse events, and
reduces asthma exacerbations in reduces asthma exacerbations in
children children ((6 to <12 years6 to <12 years) ) with with
inadequately controlled moderateinadequately controlled moderate--toto--
severe allergic asthma.severe allergic asthma.
Lanier B, et al. Lanier B, et al. J Allergy Clin Immunol 2009;124:1210J Allergy Clin Immunol 2009;124:1210--6.6.
Fig 2
Lanier B , et al. Lanier B , et al. J Allergy Clin Immunol 2009;124(6):1210J Allergy Clin Immunol 2009;124(6):1210--6.6.
Clinically significant Clinically significant
asthma exacerbation asthma exacerbation
rates over a period of rates over a period of
24 weeks (primary 24 weeks (primary
outcome; A) and 52 outcome; A) and 52
weeks (B) in patients weeks (B) in patients
with moderatewith moderate--toto--
severe asthma severe asthma
treated with addtreated with add--on on
omalizumabomalizumab
Asthma symptom reAsthma symptom re--emergence emergence
after omalizumab withdrawalafter omalizumab withdrawal
•• The reason for omalizumab being ineffective in The reason for omalizumab being ineffective in
some patients is unknown, but it is reasonable to some patients is unknown, but it is reasonable to
ask whether the ask whether the ‘‘‘‘failuresfailures’’’’ result from ineffective result from ineffective
reductions in IgE levels. reductions in IgE levels.
•• Questions are being asked about whether the dose Questions are being asked about whether the dose
can be reduced after months of treatment or can be reduced after months of treatment or
whether whether offoff--table regimens table regimens can be used.can be used.
•• Reducing omalizumab doses may result in Reducing omalizumab doses may result in increase increase
in free IgE in free IgE causing deterioration in asthma control.causing deterioration in asthma control.
Salvin RG, et al. J Allergy Clin Immunol 2009;123(1):107Salvin RG, et al. J Allergy Clin Immunol 2009;123(1):107--13.13.
MacGlashan D. MacGlashan D. J Allergy Clin Immunol 2009;123(1):114J Allergy Clin Immunol 2009;123(1):114--5.5.
Omalizumab SafetyOmalizumab Safety
•• Omalizumab is considered generally safe.Omalizumab is considered generally safe.
•• The most common adverse reaction from The most common adverse reaction from
omalizumab is injectionomalizumab is injection-- site pain and site pain and
bruising but the package insert contains bruising but the package insert contains
warnings regarding malignancies, warnings regarding malignancies,
geohelminth infections and a "black box" geohelminth infections and a "black box"
warning about anaphylaxis.warning about anaphylaxis.
Cox LS, et al. Allergy Asthma Clin Immunol 2009;5(1):4.Cox LS, et al. Allergy Asthma Clin Immunol 2009;5(1):4.
Omalizumab in allergic patients at risk Omalizumab in allergic patients at risk
of geohelminth infectionof geohelminth infection
•• A RDBPC trial from Brazil, conducted in 137 subjects (12A RDBPC trial from Brazil, conducted in 137 subjects (12––
30 years), revealed that 50% of the omalizumab group 30 years), revealed that 50% of the omalizumab group
experienced at least one intestinal geohelminth infection experienced at least one intestinal geohelminth infection
compared with 41% of the placebo subjects. compared with 41% of the placebo subjects.
•• This provides some evidence for a potential increased risk This provides some evidence for a potential increased risk
of geohelminth infection in subjects receiving of geohelminth infection in subjects receiving
omalizumab. omalizumab.
•• Omalizumab therapy did not appear to be associated with Omalizumab therapy did not appear to be associated with
increased morbidity attributable to intestinal helminthes increased morbidity attributable to intestinal helminthes
or to affect response to anithelmintics.or to affect response to anithelmintics.
Cruz AA, et al. Clin Exp Allergy 2007; 37 : 197Cruz AA, et al. Clin Exp Allergy 2007; 37 : 197––207.207.
Value of screening for helminth Value of screening for helminth
infections in patients receiving infections in patients receiving
longlong--term omalizumab therapyterm omalizumab therapy
The usefulness of screening for helminth The usefulness of screening for helminth
infections before considering omalizumab therapy infections before considering omalizumab therapy
varies widely between different exposure risk varies widely between different exposure risk
groups, and is groups, and is generally not necessary except in generally not necessary except in
individuals with continuing exposure, a past individuals with continuing exposure, a past
history of filarial or schistosomal infection, and history of filarial or schistosomal infection, and
individuals with a history or high risk of infection individuals with a history or high risk of infection
with Strongyloides.with Strongyloides.
Cooper PJ, et al. Allergy 2008;63:409Cooper PJ, et al. Allergy 2008;63:409––17.17.
Omalizumab and AnaphylaxisOmalizumab and Anaphylaxis
•• A review of postA review of post--marketing adverse events suggested that at marketing adverse events suggested that at
least least 0.2% 0.2% of patients who received omalizumab experienced of patients who received omalizumab experienced
anaphylaxis between June 2003 and December 2006. anaphylaxis between June 2003 and December 2006.
Limb SL, et al. J Allergy Clin Immunol 2007;120:1378Limb SL, et al. J Allergy Clin Immunol 2007;120:1378––81.81.
•• An Omalizumab Joint Task Force of the AAAAI and the ACAAI An Omalizumab Joint Task Force of the AAAAI and the ACAAI
concluded that the anaphylaxisconcluded that the anaphylaxis--reporting rate was 0.09% .It reporting rate was 0.09% .It
recommended an observation period of 2 hours for the first 3 recommended an observation period of 2 hours for the first 3
injections and 30 minutes for subsequent injections as well as injections and 30 minutes for subsequent injections as well as
patient education regarding anaphylaxis. patient education regarding anaphylaxis.
Cox L, et al. AAAAI/ACAAI Joint Task Force Report on omalizumabCox L, et al. AAAAI/ACAAI Joint Task Force Report on omalizumab--
associated anaphylaxis. J Allergy Clin Immunol 2007;120:1373associated anaphylaxis. J Allergy Clin Immunol 2007;120:1373––7.7.
•• Another reported incidence of anaphylaxis was 0.14% in Another reported incidence of anaphylaxis was 0.14% in
omalizumabomalizumab--treated patients and 0.07% in control patients. treated patients and 0.07% in control patients.
Corren J, et al. Clin Exp Allergy 2009;39:788Corren J, et al. Clin Exp Allergy 2009;39:788--97.97.
Omalizumab and MalignancyOmalizumab and Malignancy
•• Current clinical trial data do not support an increased risk Current clinical trial data do not support an increased risk
of malignant neoplasia or thrombocytopenia with of malignant neoplasia or thrombocytopenia with
omalizumab. omalizumab.
Corren J, et al. Clin Exp Allergy 2009;39(6):788Corren J, et al. Clin Exp Allergy 2009;39(6):788--97.97.
•• No cases were considered drugNo cases were considered drug--related by a panel of related by a panel of
blinded independent oncologists. The majority of cases blinded independent oncologists. The majority of cases
(60%) were diagnosed within 6 months of treatment(60%) were diagnosed within 6 months of treatment
Cox LS, et al. Allergy Asthma Clin Immunol 2009;5(1):4.Cox LS, et al. Allergy Asthma Clin Immunol 2009;5(1):4.
•• A multicenter, prospective, observational cohort study A multicenter, prospective, observational cohort study
designed to evaluate the long term safety of Xolairdesigned to evaluate the long term safety of Xolair®®
(omalizumab) is currently in progress.(omalizumab) is currently in progress.
http://clinicaltrials.gov/ct2/show/NCT00252135?term=omalizumabhttp://clinicaltrials.gov/ct2/show/NCT00252135?term=omalizumab
ChurgChurg--Strauss syndrome in Strauss syndrome in
patients treated with omalizumabpatients treated with omalizumab
Omalizumab treatment may unmask CSS Omalizumab treatment may unmask CSS
in patients who have an underlying in patients who have an underlying
eosinophilic disorder due to withdrawal eosinophilic disorder due to withdrawal
of corticosteroids in favor of omalizumab, of corticosteroids in favor of omalizumab,
or may delay corticosteroid treatment or may delay corticosteroid treatment
allowing for CSS to manifest.allowing for CSS to manifest.
Wechsler ME, et al. Chest 2009;136;507Wechsler ME, et al. Chest 2009;136;507--18.http://chestjournal.chestpubs. 18.http://chestjournal.chestpubs.
org/ content/136/2/507.full.htmlorg/ content/136/2/507.full.html
Antibodies specific for a segment of human Antibodies specific for a segment of human
membrane IgE deplete IgEmembrane IgE deplete IgE--producing B cells producing B cells
in humanized micein humanized mice
•• Although efficacious, current therapeutic IgEAlthough efficacious, current therapeutic IgE--
specific antibodies specific antibodies do not appear to affect IgE do not appear to affect IgE
productionproduction and therefore must be given and therefore must be given
frequently and chronically to maintain sufficient frequently and chronically to maintain sufficient
suppression of serum IgE.suppression of serum IgE.
•• Recently, a strategy was developed to disrupt IgE Recently, a strategy was developed to disrupt IgE
production by generating MAbs that target a production by generating MAbs that target a
segment of membrane IgE on segment of membrane IgE on human IgEhuman IgE--switched switched
B cellsB cells that is not present in serum IgE.that is not present in serum IgE.
•• This may provide a novel treatment for asthma This may provide a novel treatment for asthma
and allergyand allergy
Brightbill HD, et al. J Clin Invest 2010;120(6):2218Brightbill HD, et al. J Clin Invest 2010;120(6):2218––29.29.
•• ILIL--5 is believed to be a key cytokine in 5 is believed to be a key cytokine in
eosinophil function at sites of allergic eosinophil function at sites of allergic
inflammation.inflammation.
•• Humanized monoclonal antibodies against Humanized monoclonal antibodies against
ILIL--5 have been synthesized. 5 have been synthesized.
•• One such antibody, One such antibody, mepolizumabmepolizumab, is a high, is a high--
affinity humanized, nonaffinity humanized, non––complementcomplement--fixing fixing
monoclonal antibody (IgG1) specific for monoclonal antibody (IgG1) specific for
human ILhuman IL--5.5.
FloodFlood--Page P, et al. Am J Respir Crit Care Med 2007;176:1062Page P, et al. Am J Respir Crit Care Med 2007;176:1062––71. 71.
MepolizumabMepolizumab (anti(anti--ILIL--5 ab) 5 ab)
•• Pilot studies of antiPilot studies of anti––ILIL--5 therapy showed 5 therapy showed
profound reduction in both circulating and profound reduction in both circulating and
sputum eosinophils.sputum eosinophils.
•• However, in contrast to the results of animal However, in contrast to the results of animal
studies, there was no significant effect of ILstudies, there was no significant effect of IL--5 5
blockade on either AHR or the late asthmatic blockade on either AHR or the late asthmatic
response after allergen challenge, or sustained response after allergen challenge, or sustained
effect on lung function.effect on lung function.
Leckie MJ, et al. Lancet 2000; 356:2144Leckie MJ, et al. Lancet 2000; 356:2144––8.8.
Kips JC, et al. Am J Respir Crit Care Med 2003;167:1655Kips JC, et al. Am J Respir Crit Care Med 2003;167:1655––9.9.
FloodFlood--Page PT, et al. Am J Respir Crit Care Med 2003;167:199Page PT, et al. Am J Respir Crit Care Med 2003;167:199––
204.204.
MepolizumabMepolizumab (cont(cont’’d)d)
A study to evaluate safety and A study to evaluate safety and
efficacy of mepolizumab in patients efficacy of mepolizumab in patients
with moderate persistent asthmawith moderate persistent asthma
Mean values for blood eosinophilsMean values for blood eosinophils
FloodFlood--Page P, et al. Am J Respir Crit Care Med 2007;176:1062Page P, et al. Am J Respir Crit Care Med 2007;176:1062––71. 71.
A higher proportion of patients in A higher proportion of patients in
the placebo and mepolizumab 250the placebo and mepolizumab 250--
mg treatment groups had an mg treatment groups had an
exacerbation of any level of severity exacerbation of any level of severity
during the study, compared with during the study, compared with
the mepolizumab 750the mepolizumab 750--mg treatment mg treatment
group.group.
FloodFlood--Page P, et al. Am J Respir Crit Care Med 2007;176:1062Page P, et al. Am J Respir Crit Care Med 2007;176:1062––71. 71.
A study to evaluate safety and A study to evaluate safety and
efficacy of mepolizumab in patients efficacy of mepolizumab in patients
with moderate persistent asthmawith moderate persistent asthma
The Demise of AntiThe Demise of Anti––ILIL--5 for Asthma, or Not!5 for Asthma, or Not!
•• AntiAnti––ILIL--5 has proven to be useful in managing 5 has proven to be useful in managing
hyperhyper--eosinophilic syndromeseosinophilic syndromes..
•• The results of clinical trials in patients with The results of clinical trials in patients with
asthma with airway eosinophilia and poor asthma with airway eosinophilia and poor
controlcontrol, which are underway, are eagerly , which are underway, are eagerly
awaited, because they have implications not awaited, because they have implications not
only for the possible role of antionly for the possible role of anti––ILIL--5 as a 5 as a
therapy for asthma but also in clarifying the therapy for asthma but also in clarifying the
role of airway eosinophils in its pathorole of airway eosinophils in its patho--biology.biology.
OO’’Byrne PMByrne PM. . Am J Respir Crit Care Med 2007;176:1059Am J Respir Crit Care Med 2007;176:1059––61.61.
Mepolizumab and Mepolizumab and
Exacerbations of Refractory Exacerbations of Refractory
Eosinophilic AsthmaEosinophilic Asthma
Severe Exacerbations during the Severe Exacerbations during the
Course of the Study. Course of the Study.
Panel A Panel A shows the cumulative shows the cumulative
number of severe exacerbations number of severe exacerbations
that occurred in each study that occurred in each study
group over the course of 50 group over the course of 50
weeks. weeks.
Panel B Panel B shows the distribution of shows the distribution of
the number of exacerbations the number of exacerbations
among subjects in each group among subjects in each group
during the treatment period.during the treatment period.Haldar P, et al. N Engl J Med Haldar P, et al. N Engl J Med
2009;360:9732009;360:973--84.84.
RECENT DATARECENT DATA
Mepolizumab for PrednisoneMepolizumab for Prednisone--Dependent Asthma with Dependent Asthma with
Sputum EosinophiliaSputum Eosinophilia
Proportion of Patients without an Asthma Exacerbation during theProportion of Patients without an Asthma Exacerbation during the StudyStudy
Nair P, et al. N Engl J Med 2009;360:985Nair P, et al. N Engl J Med 2009;360:985--93.93.
RECENT DATARECENT DATA
Eosinophils in Asthma Eosinophils in Asthma —— Closing the Loop or Closing the Loop or
Opening the Door?Opening the Door?
•• Over the years, eosinophils were identified as a Over the years, eosinophils were identified as a
prominent cell type in asthma, yet their role as either prominent cell type in asthma, yet their role as either
an an ““effectoreffector”” or or ““innocent bystanderinnocent bystander”” was not was not
confirmed.confirmed.
•• Recent studies confirm that in a subgroup of patients Recent studies confirm that in a subgroup of patients
with eosinophilic asthma, with eosinophilic asthma, mepolizumab therapy had mepolizumab therapy had
some clinical benefitsome clinical benefit. .
•• However, many patients with asthma However, many patients with asthma do not have do not have
eosinophiliaeosinophilia, and even in patients with eosinophilic , and even in patients with eosinophilic
asthma, mepolizumab had asthma, mepolizumab had no effect on other no effect on other
physiological and clinical factorsphysiological and clinical factors. .
Wenzel SE. N Engl J Med 2009;360;1026Wenzel SE. N Engl J Med 2009;360;1026--8.8.
•• Positive results in treating asthma patients were Positive results in treating asthma patients were
challenged by other researches. challenged by other researches.
•• There is also concern about serious problems and There is also concern about serious problems and
adverse events related to that kind of treatment adverse events related to that kind of treatment
especially in children.especially in children.
•• However, research on antiHowever, research on anti--TNFTNF--alpha and asthma alpha and asthma
underlined a significant polymorphism in asthma underlined a significant polymorphism in asthma
phenotypes. phenotypes.
•• Therapy with antiTherapy with anti--TNFTNF--alpha should be limited to a alpha should be limited to a
small subgroup of patients with a specific phenotype small subgroup of patients with a specific phenotype
manifested by an increased TNF axis. manifested by an increased TNF axis.
Gjurow D, et al. Recent Pat Inflamm Allergy Drug Discov 2009;3(2Gjurow D, et al. Recent Pat Inflamm Allergy Drug Discov 2009;3(2):143):143--8.8.
AntiAnti––Tumor Necrosis FactorTumor Necrosis Factor--alpha in Asthma Therapyalpha in Asthma Therapy
The Effects of a Monoclonal The Effects of a Monoclonal
Antibody Directed againstAntibody Directed against
TNFTNF--alpha in Asthma (Infliximab)alpha in Asthma (Infliximab)
Exacerbations of AsthmaExacerbations of Asthma
The authors concluded that infliximab caused a decrease in the The authors concluded that infliximab caused a decrease in the
number of exacerbations in symptomatic moderate asthma. number of exacerbations in symptomatic moderate asthma.
Erin EM, et al. Am J Respir Crit Care Med 2006;174:735Erin EM, et al. Am J Respir Crit Care Med 2006;174:735––62.62.
A randomized DBPC study of A randomized DBPC study of
TNFTNF--alpha blockade in severe alpha blockade in severe
persistent asthma (Golimumab)persistent asthma (Golimumab)
Change from baseline in preChange from baseline in pre--bronchodilator percentbronchodilator percent--predicted FEV1.predicted FEV1.
The authors concluded that treatment with golimumab did not The authors concluded that treatment with golimumab did not
demonstrate a favorable riskdemonstrate a favorable risk––benefit profile.benefit profile.
Wenzel SE, et al. Am J Respir Crit Care Med 2009;179:549Wenzel SE, et al. Am J Respir Crit Care Med 2009;179:549––58.58.
Correspondence: Correspondence:
AntiAnti––TNFTNF--alpha in Asthmaalpha in Asthma
•• The incidence of antiThe incidence of anti––TNFTNF-- induced induced tuberculosistuberculosis can be as can be as
high as 224/100,000 treated patients. Manifestations are high as 224/100,000 treated patients. Manifestations are
often extraoften extra--pulmonary, and in 24% of the cases there is pulmonary, and in 24% of the cases there is
disseminated disease with a significant risk of death. disseminated disease with a significant risk of death.
•• The riskThe risk--benefit should be carefully considered as the benefit should be carefully considered as the
protective effect of such treatment is estimated not to be protective effect of such treatment is estimated not to be
higher than higher than 60%60%..
•• Therefore, studies on the therapeutic value of antiTherefore, studies on the therapeutic value of anti--TNF in TNF in
asthma should be focused on patients with severe asthma should be focused on patients with severe
debilitating disease. debilitating disease.
Krouwels FH. Am J Respir Crit Care Med 2007;175(3):288.Krouwels FH. Am J Respir Crit Care Med 2007;175(3):288.
•• The occurrence of neutralizing antibodies The occurrence of neutralizing antibodies
against infliximab is a common event, and against infliximab is a common event, and
this may compromise drug efficacy. this may compromise drug efficacy.
•• Large multicenter, placeboLarge multicenter, placebo--controlled, controlled,
randomized, controlled trials in patients randomized, controlled trials in patients
with severe chronic asthma are required with severe chronic asthma are required
before setting any recommendations.before setting any recommendations.
Edwards CJ, Polosa R. Am J Respir Crit Care Med 2007;175(2Edwards CJ, Polosa R. Am J Respir Crit Care Med 2007;175(2):196.):196.
Correspondence: Correspondence:
Study of infliximab Study of infliximab
treatment in asthmatreatment in asthma
AntiAnti--TGF beta MAbTGF beta MAb
•• Neutralization of TGFNeutralization of TGF--b1 b1
with specific antibody with specific antibody
had no significant effect had no significant effect
on airway inflammation on airway inflammation
and eosinophilia and eosinophilia
•• It also enhanced It also enhanced
ovalbumin induced AHR ovalbumin induced AHR
•• It suppressed pulmonary It suppressed pulmonary
fibrosis.fibrosis.
Alcorn JF, et al. Am J Respir Crit Care Med Alcorn JF, et al. Am J Respir Crit Care Med
2007;176:9742007;176:974––82.82.
Daclizumab improves asthma control Daclizumab improves asthma control
in patients with moderate to severe in patients with moderate to severe
persistent asthma: a RDBPC trialpersistent asthma: a RDBPC trial
The use of daclizumab, an antiThe use of daclizumab, an anti--CD25 antibody, was associated with some CD25 antibody, was associated with some
improvement in lung function and asthma control along with a redimprovement in lung function and asthma control along with a reduction in uction in
blood eosinophils.blood eosinophils.
Busse WW, et al. Am J Respir Crit Care Med 2008;178:1002Busse WW, et al. Am J Respir Crit Care Med 2008;178:1002––8.8.
•• A mutated interleukinA mutated interleukin--4 (pitrakinra) that 4 (pitrakinra) that
binds the ILbinds the IL--4R4Rαα and blocks the effects of and blocks the effects of
both ILboth IL--4 and IL4 and IL--13 has been developed. 13 has been developed.
•• A small RDBPC phase II trial in mildA small RDBPC phase II trial in mild--toto--
moderate asthmatics showed that inhaled moderate asthmatics showed that inhaled
pitrakinrapitrakinra reduced the late phase decline in reduced the late phase decline in
lung function in response to inhalational lung function in response to inhalational
allergen challenge with no serious adverse allergen challenge with no serious adverse
events.events.
Wenzel SE, et al. Lancet 2007;370:1422Wenzel SE, et al. Lancet 2007;370:1422––31.31.
Other Potential MAbs in Asthma Other Potential MAbs in Asthma
TherapyTherapy
Other potential MAbs in asthma therapy (contOther potential MAbs in asthma therapy (cont’’d)d)
•• A phase 1 study evaluating the A phase 1 study evaluating the
pharmacokinetics, safety and tolerability of a pharmacokinetics, safety and tolerability of a
human human ILIL--13 antibody 13 antibody (CAT(CAT--354) in asthma 354) in asthma
revealed an acceptable safety profile. revealed an acceptable safety profile.
Singh D, et al. BMC Pulm Med 2010;10:3.Singh D, et al. BMC Pulm Med 2010;10:3.
•• Specific inhibition of Specific inhibition of tissue kallikrein 1 tissue kallikrein 1 with a with a
human monoclonal antibody (DXhuman monoclonal antibody (DX--2300 ) 2300 )
revealed a potential in vitro and in vivo role revealed a potential in vitro and in vivo role
in airway diseases.in airway diseases.
Sexton DJ, et al. Sexton DJ, et al. Biochem J 2009;422(2):383Biochem J 2009;422(2):383--92.92.
Other potential MAbs in asthma therapy (contOther potential MAbs in asthma therapy (cont’’d)d)
•• THTH--17 cells may contribute to the 17 cells may contribute to the
pathogenesis of TH2pathogenesis of TH2--mediated allergic mediated allergic
diseases, increase neutrophil infiltration diseases, increase neutrophil infiltration
and mucus proteins, and is associated with and mucus proteins, and is associated with
a steroida steroid--resistant asthma phenotype. resistant asthma phenotype.
Targeting THTargeting TH--17 17 cells may be of value in cells may be of value in
severe neutrophilic asthma.severe neutrophilic asthma.
•• In animal studies, In animal studies, a neutralizing antibody a neutralizing antibody
against ILagainst IL--2525 abrogates AHR, reduces ILabrogates AHR, reduces IL--5 5
and ILand IL--13 production, reduces tissue 13 production, reduces tissue
eosinophil infiltration, and serum IgE. eosinophil infiltration, and serum IgE.
Long AA. MAbs 2009; 1(3):237Long AA. MAbs 2009; 1(3):237--46.46.
•• In vivo treatment with an In vivo treatment with an antianti--CD147 MAb CD147 MAb
significantly reduced the accumulation of significantly reduced the accumulation of
eosinophils and antigeneosinophils and antigen--specific Th2 specific Th2
cytokine secretion in lung tissues, airway cytokine secretion in lung tissues, airway
epithelial mucin production, and AHR to epithelial mucin production, and AHR to
methacholine challenge. methacholine challenge.
Gwinn WM, et al. Gwinn WM, et al. J Immunol J Immunol 2006;177(7):48702006;177(7):4870––9.9.
•• Complexes of ILComplexes of IL--2 / anti2 / anti--ILIL--2 MAb2 MAb, in a , in a
murine asthma model, reduced the severity murine asthma model, reduced the severity
of allergenof allergen--induced inflammation in the induced inflammation in the
lung by expanding Tregs.lung by expanding Tregs.
Wilson MS, et al. Wilson MS, et al. J Immunol 2008;181(10):6942J Immunol 2008;181(10):6942––54.54.
Other potential MAbs in asthma therapy (contOther potential MAbs in asthma therapy (cont’’d)d)
Other potential MAbs in asthma therapy (contOther potential MAbs in asthma therapy (cont’’d)d)
•• T cell, immunoglobulin, mucin (TIM) T cell, immunoglobulin, mucin (TIM)
genes are associated with several genes are associated with several
atopic diseases.atopic diseases.
•• A A MAb against TIMMAb against TIM--1 protein 1 protein
influenced activated T cells and influenced activated T cells and
blocked the development of disease in blocked the development of disease in
a humanized mouse model of allergic a humanized mouse model of allergic
asthma suggesting that it may provide asthma suggesting that it may provide
potent therapeutic benefit in asthmapotent therapeutic benefit in asthma
Sonar SS. J Clin Invest 2010;120(8):2767Sonar SS. J Clin Invest 2010;120(8):2767--81.81.
Limitations of Use of MAbs in AsthmaLimitations of Use of MAbs in Asthma
•• Expense Expense
•• Parenteral administration Parenteral administration
•• Adverse effects Adverse effects
•• Host antiHost anti--drug responses limiting drug responses limiting
ongoing therapy ongoing therapy
•• Limitations in current concepts of Limitations in current concepts of
molecular pathogenesis of disease molecular pathogenesis of disease
Take Home MessageTake Home Message
•• The costThe cost--effectiveness and adverse events effectiveness and adverse events associated with the use of each associated with the use of each monoclonal antibody should be monoclonal antibody should be considered. considered.
•• This could be achieved by carefully This could be achieved by carefully revising the existing clinical trials in light of revising the existing clinical trials in light of solid evidencesolid evidence--based criteria.based criteria.
•• Pediatric data on cytokinePediatric data on cytokine--specific specific monoclonal antibody therapies are still monoclonal antibody therapies are still needed. needed.