Monoclonal Antibodies in Asthma Therapy - World Allergy Organization

Monoclonal Monoclonal

Antibodies in Asthma Antibodies in Asthma

TherapyTherapy

Yehia ElYehia El--Gamal Gamal

MD, PhDMD, PhD

Conflict of InterestConflict of Interest

Nothing to discloseNothing to disclose

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


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.


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.


•• 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.



•• 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.

Thank Thank

YouYou

Yehia Yehia

ElEl--GamalGamal

Monoclonal Antibodies in Asthma Therapy - World Allergy Organization

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