J ALLERGY CLIN IMMUNOL

FEBRUARY 2011

AB164 Abstracts

MONDAY

623 Reduction of Total IgE by Targeted Coengagement of IgE-BCRand FcgRIIb with Fc-Engineered Antibodies

J. Desjarlais, S. Chu, H. Horton, H. Chen, S. Karki, I. Leung, D. Szym-

kowski; Xencor, Inc., Monrovia, CA.

RATIONALE: An IgE-mediated allergic response requires allergen-spe-

cific B-cell differentiation into IgE-producing plasma cells. We created

XmAb7195, an omalizumab (Xolair) -related anti-IgE antibody Fc engi-

neered for high affinity to human FcgRIIb, to coengage IgE-BCR and

FcgRIIb and prevent activation and terminal differentiation of IgE1 B

cells. Our hypothesis is that XmAb7195 will not only sequester free IgE,

but will suppress its production and reduce total IgE.

METHODS:We humanized mouse anti-human IgE antibody MaE11 and

added the inhibitory Fc described in Chu et al. Molecular Immunology

45:3926-3933 (2008) to create XmAb7195. An anti-mouse surrogate anti-

body XENP8253 and an IgG1 comparator (Xolair surrogate) XENP8252

were also generated from the antibody R1E4. Effects of XmAb7195 on to-

tal IgE were assessed in SCIDmice engrafted with human PBMCs. Effects

of XENP8252 versus XENP8253 on free and total IgEwere assessed in hu-

man FcgRIIb transgenic mice.

RESULTS: XmAb7195 suppressed total IgE levels in huPBMC-SCID

mice relative to PBS control (p < 0.01) and Xolair (p < 0.01) by ;30-

fold. Control antibodies lacking affinity for FcgRIIb increased total IgE

;5-fold. In huFcgRIIb transgenic mice, the FcgRIIb-enhanced antibody

XENP8253 suppressed total IgE ;40-fold relative to PBS control (p <

0.01) versus 6-fold for the Xolair surrogate XENP8252.

CONCLUSIONS:A novel antibody that recruits FcgRIIb to IgE-BCR via

its enhanced Fc domain rapidly decreases free IgE like omalizumab, but

unlike omalizumab also decreases total IgE. Inhibition of B cell differen-

tiation into IgE-secreting plasma cells may represent an improved thera-

peutic option for greater and sustained reduction of IgE levels.

624 Predictive and Pharmacodynamic Biomarkers of Interleukin-13 Blockade: Effect of Lebrikizumab on Late Phase AsthmaticResponse to Allergen Challenge

H. Scheerens1, J. R. Arron1, Z. Su1, Y. Zheng1, W. Putnam1, R. W. Erick-

son1, D. F. Choy1, J. H. Lee1, J. M. Harris1, N. N. Jarjour2, J. G. Mat-

thews1; 1Genentech, South San Francisco, CA, 2University of

Wisconsin, School of Medicince and Public Health, Madison, WI.

RATIONALE: IL13 is considered an attractive therapeutic target for

asthma, although pathophysiological heterogeneity may limit the effec-

tiveness of IL13 blocking agents to only a subset of asthmatics. We as-

sessed lebrikizumab, a humanized monoclonal antibody against IL13, in

mild asthmatics with bronchial allergen challenge and serum pharmacody-

namic and predictive biomarkers.

METHODS: Phase II randomized, double-blind, placebo-controlled

study; 5 mg/kg lebrikizumab:placebo (1:1 ratio) subcutaneously q4 weeks

for 12 weeks. Primary outcome measure: allergen-induced late asthmatic

response (LAR) atWeek 13.We assessed serum biomarkers to demonstrate

IL13 pathway inhibition and to identify patients with an increased benefit

from lebrikizumab. ClinicalTrials.gov, NCT00781443.

RESULTS: 28 patients were included in analysis of the primary endpoint

(n516 placebo, 12 lebrikizumab). AtWeek 13, the AUC of the LAR in leb-

rikizumab-treated patients was reduced by 48% vs. placebo (95% CI: -19-

90%), with no effect on the early phase response and a small effect on

methacholine reactivity with mean post allergen PC20 in the lebrikizumab

group 0.33 doubling doses higher than placebo (95% CI: -0.64,1.30).

Lebrikizumab treatment clearly exerted systemic effects on markers of

Th2 inflammation, with placebo-adjusted reductions of 20-25% in serum

IgE, CCL13, and CCL17. Subjects with baseline levels above the median

of peripheral blood eosinophils, serum IgE, or serum periostin exhibited a

greater placebo-adjusted lebrikizumab dependent reduction in LAR than

subjects with baseline levels of these biomarkers below the median.

CONCLUSIONS: Therapeutic blockade of IL13 may be an effective

treatment for allergic asthma and the magnitude of clinical response to leb-

rikizumab treatment may be predicted from systemic biomarker levels.

625 Co-associations between IL33 Gene Variants andSchistosoma mansoni Infection and Asthma

L. Gao1, M. I. Araujo2, J. V. Cordell1, N. Rafaels1, C. Vergara1, M. Camp-

bell1, A. V. Grant1, E. V. Ponte2, R. R. Oliveira2, A. A. Cruz2, E. M. Car-

valho2, T. H. Beaty3, R. A. Mathias1, K. C. Barnes1; 1Division of Allergy

and Clinical Immunology, Johns Hopkins University, Baltimore, MD,2Servico de Imunologia, Hospital Universit�ario Professor Edgard Santos,

Bahia, BRAZIL, 3Johns Hopkins Bloomberg School of Public Health,

Baltimore, MD.

RATIONALE: Interleukin-33 (IL-33), a cytokine expressed mainly by fi-

broblasts, epithelial, and endothelial cells following pro-inflammatory

stimulation and released upon cell necrosis, is considered to be crucial

for inducing Th2-type cytokine associated immune responses in allergic

diseases and host defense against parasites. Genome-wide association

studies (GWAS) identified single nucleotide polymorphisms (SNPs) flank-

ing the IL33 gene associated with asthma. We tested for association be-

tween IL33 variants and Schistosoma mansoni infection in Brazilian

families, and risk of asthma in two independent populations (African

American and African Caribbean).

METHODS:A total of 822 individuals were enrolled from a schistosomi-

asis-endemic area in Brazil and two quantitative traits, total serum IgE

(tIgE) level and egg count, were analyzed using FBAT. A meta-analysis

was performed combining the two asthmatic populations of African ances-

try. We also genotyped 23 additional SNPs previously reported to be asso-

ciated with asthma.

RESULTS: Two IL33 SNPs (rs17498196 and rs16924241) were associ-

ated with tIgE level (p50.001 and 0.027, respectively) among these

Brazilian families. SNP rs1342326, a marker associated with risk of

asthma in a previous GWAS study, appeared to be protective for helminthic

infection as measured by stool egg count (p50.02). SNP rs7861831

showed evidence of association with asthma (p50.006) and wheeze

(p50.02). Additional SNPs in IL33 (rs3939286 and rs10975501) were

also associated with asthma in the populations of African descent

(p50.0028 and 0.001, respectively).

CONCLUSIONS: Our findings suggest markers in IL33 are associated

with protection to S. mansoni infection in a schistosomiasis-endemic

Brazilian population, and risk to asthma in populations of African descent.

626 A Prospective Sudy of Asthma and its Related PhenotypesL. M. Fine, M. N. Blumenthal; University of Minnesota, Min-

neapolis, MN.

RATIONALE: A prospective investigation of probands with asthma and

their nuclear families was performed using the CSGA study families.

Our hypothesis was that the phenotypes might change with time and thus

affect genetic studies.

METHODS: 85 subjects were evaluated in 1995 and 2007 regarding

changes in the following phenotypes: Asthma, defined as 2 or more symp-

toms (cough, wheeze, shortness of breath) in addition to reversibly of

FEV1 (12% or greater) following the use of a beta agonist and/or a positive

methacholine challenge; Atopy, defined as 1 or more positive skin tests to

14 of the common aeroallergens or total IgE level above or below 100 IU/

mL.

RESULTS:Of 85 subjects we have duplicated results for asthma diagnosis

for 65 subjects. In 1995, 27 had asthma and in 2007, 22 had asthma. 7 sub-

jects became positive, 12 became negative, 15 remained positive and 33 re-

mained negative for asthma. For IgE levels, initially 36 of 84 were > 100

IU/mL (positive) and when tested the second time only 6 were positive. No

subjects became positive, 6 remained positive, 48 remained negative and

30 became negative. When skin tests were evaluated, 56 were positive ini-

tially for 1 or more reactions and when tested a second time 67 were pos-

itive. None who were initially positive became negative. 56 remained

positive, 11 became positive and 16 remained negative.

CONCLUSION:Asthma and related phenotypes vary with time. This will

likely impact the utility and interpretation of genetic studies that rely on

phenotypes.