EP4652461A2 - Dosages pour déterminer des allergies au lait - Google Patents

Dosages pour déterminer des allergies au lait

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Publication number
EP4652461A2
EP4652461A2 EP24745049.7A EP24745049A EP4652461A2 EP 4652461 A2 EP4652461 A2 EP 4652461A2 EP 24745049 A EP24745049 A EP 24745049A EP 4652461 A2 EP4652461 A2 EP 4652461A2
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EP
European Patent Office
Prior art keywords
milk
seq
subject
alphas2
chance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
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EP24745049.7A
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German (de)
English (en)
Inventor
Paul Kearney
Heather Butler
Clive Hayward
Robert C. Getts
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Allergenis Inc
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Allergenis Inc
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Publication date
Application filed by Allergenis Inc filed Critical Allergenis Inc
Publication of EP4652461A2 publication Critical patent/EP4652461A2/fr
Pending legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders

Definitions

  • the present disclosure is directed, in part, to methods of determining the milk phenotype of a subject, methods of determining prior to initiating oral immunotherapy (OIT) in a subject whether the subject will experience sustained unresponsiveness (S U) after completion of the OIT, and methods of determining a milk allergy threshold amount for a subject.
  • OIT oral immunotherapy
  • Milk phenotype refers to differentiating milk allergic subjects who are allergic to baked milk and those who are not. This is an important distinction in milk allergic patients for several reasons. First, in day-to-day life, those who are not baked milk allergic can safely consume baked products containing milk (e.g., muffins, bread, etc.) from those who cannot. Second, those who are not baked milk allergic are more likely to outgrow their milk allergy. Accurate phenotyping of milk allergic patients is critical for establishing an allergy management program including dietary and therapeutic options. Currently, phenotyping can only be established through oral food challenges.
  • OIT Oral Immunotherapy
  • milk allergy management is avoidance.
  • the present disclosure provides methods of determining the milk phenotype of a subject, the methods comprising determining the level of antibody reactivity in a sample of blood obtained from the subject to one or more milk epitopes chosen from alphas2-10 (INPSKENLC STFCKEVVRNA, SEQ ID NO: 1), betacas-53 (FPPQSVLSLSQSKVLPVPQK, SEQ ID NO: 2), alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3), kappacas-41 (TINTIASGEP TSTPTTEAVE, SEQ ID NO: 4), betalac-43 (EVDDEALEKFDKALKALPMH, SEQ ID NO: 5), and betalac-44 (DEALEKFDKALKALPMHIRL, SEQ ID NO: 6); wherein an antibody reactivity above a threshold indicates the subject has a baked milk allergic milk phenotype, and an antibody reactivity’ at or below the threshold indicates the subject does not have a baked milk allergic milk
  • the present disclosure also provides methods of determining prior to initiating oral immunotherapy (OIT) in a subject whether the subject will experience sustained unresponsiveness (SU) after completion of the OIT, the methods comprising determining the level of antibody reactivity in a sample of blood obtained from the subject to alphas2-10 (INP SKENLCSTFCKEVVRNA, SEQ ID NO: 1) or alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3), or a combination thereof; wherein a high antibody reactivity indicates the subject has a low chance of achieving SU, a medium antibody reactivity indicates the subject has a medium chance of achieving SU, and a low antibody reactivity indicates the subject has a high chance of achieving SU.
  • OIT oral immunotherapy
  • the present disclosure also provides methods of determining a milk allergy threshold amount for a subject, the methods comprising determining the level of antibody reactivity in a sample of blood obtained from the subject to a combination of: i) betacas-33 (KVKEAMAP KHKEMPFPKYPV.
  • Figure 1 shows the alphas2-8,10,13 alignment with P02663 (first 80 amino acids out of 222).
  • Figure 2 shows a boxplot of baked milk allergic vs. whole milk (i.e., milk allergic but not baked milk allergic) subjects in the Vietnamese milk study and their stratification by alphas2-10 (IgE reactivity) and alphas2-13 (IgGE reactivity) (left); and an AUCROC for the same epitope pairing demonstrating an AUC of 95% and optimal sensitivity and specificity of 91% and 94%, respectively (right).
  • IgE reactivity alphas2-10
  • IgGE reactivity alphas2-13
  • Figure 3 shows stratification of patients by alphas2-10 (IgE reactivity) alone for the cohorts of Baked Milk Allergic and Whole Milk (milk allergic but not baked milk allergic); another cohort, Outgrown (subjects who outgrew their milk allergy), was included as a reference; the boxplot demonstrates the ability of alphas2-10 to stratify patients by phenotype.
  • Figure 4 shows placement of subjects into a low and high milk tolerance group based on the IgE reactivity of two epitopes allows for a tolerance profile for each group to be derived.
  • Figure 5 shows placement of subjects into a low and high milk tolerance group based on the IgE reactivity of alphas 1-54 and alphas 1-55 at a threshold of 1.0.
  • Figure 6 shows placement of subjects into a low and high milk tolerance group based on the IgE reactivity of alphasl-35 and s2-26 at a threshold of 1.2.
  • the present disclosure provides methods and compositions for determining whether sequential (linear) epitope-specific IgE (ses-IgE) profiling can accurately phenotype baked milk allergic patients vs. baked milk tolerant allergic patients.
  • sequential (linear) epitope-specific IgE (ses-IgE) profiling can accurately phenotype baked milk allergic patients vs. baked milk tolerant allergic patients.
  • ses-IgE sequential epitope-specific IgE profiling
  • the present disclosure provides methods of determining the milk phenotype of a subject, the methods comprising determining the level of antibody reactivity in a sample of blood obtained from the subject to one or more milk epitopes chosen from alphas2-10 (INPSKENLC STFCKEVVRNA, SEQ ID NO: 1), betacas-53 (FPPQSVLSLSQSKVLPVPQK, SEQ ID NO: 2), alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3), kappacas-41 (TINTIASGEP TSTPTTEAVE, SEQ ID NO: 4), betalac-43 (EVDDEALEKFDKALKALPMH, SEQ ID NO: 5), and betalac-44 (DEALEKFDKALKALPMHIRL, SEQ ID NO: 6).
  • alphas2-10 IPSKENLC STFCKEVVRNA, SEQ ID NO: 1
  • betacas-53 FPPQSVLSLSQSKVLPVPQK, SEQ ID NO:
  • the sample obtained from the subject can be any sample whereby antibody reactivity to milk peptides can be detected and measures.
  • the sample is blood.
  • the sample is serum.
  • Determining the level of antibody reactivity' can be carried out by any assay that measures the level of reactivity between an antibody in a subject to a milk peptide.
  • the assay is a bead-based epitope assay (BBEA).
  • the one or more milk epitopes can be chosen from alphas2-10 (INPSKENLCSTFC KEVVRNA, SEQ ID NO: 1), betacas-53 (FPPQSVLSLSQSKVLPVPQK, SEQ ID NO: 2), alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3), kappacas-41 (TINTIASGEPTS TPTTEAVE. SEQ ID NO: 4), betalac-43 (EVDDEALEKFDKALKALPMH. SEQ ID NO: 5), and betalac-44 (DEALEKFDKALKALPMHIRL, SEQ ID NO: 6), or any combination thereof.
  • the level of reactivity' is determined between an antibody and alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1). In some embodiments, the level of reactivity is determined between an antibody and betacas-53 (FPPQSVLSLSQSKVLPVPQK, SEQ ID NO: 2). In some embodiments, the level of reactivity is determined between an antibody and alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3). In some embodiments, the level of reactivity is determined between an antibody and kappacas-41 (TINTIASGEPTSTPTTEAVE, SEQ ID NO: 4).
  • the level of reactivity is determined between an antibody and betalac-43 (EVDDEALEKFDKALKALPMH, SEQ ID NO: 5). In some embodiments, the level of reactivity is determined between an antibody and betalac-44 (DEALEKFDKALKAL PMHIRL, SEQ ID NO: 6).
  • the one or more milk epitopes can be chosen from a pair of milk epitopes chosen from: i) alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and betacas-53 (FPPQSVLSLSQ SKVLPVPQK, SEQ ID NO: 2); u) alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3) and kappacas-41 (TINTIASGEPTSTPTTEAVE, SEQ ID NO: 4); in) alphas2-10 (INPSKENLC STFCKEVVRNA, SEQ ID NO: 1) and betalac-43 (EVDDEALEKFDKALKALPMH, SEQ ID NO: 5); iv) alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and betalac-44 (DE ALEKFDKALKALPMHIRL, SEQ ID NO: 6); v) alphas2-10 (INPSKENLCSTFCKEV
  • the pair of milk epitopes are alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and betacas-53 (FPPQSVLSLSQS KVLPVPQK, SEQ ID NO: 2).
  • the pair of milk epitopes are alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3) and kappacas-41 (TINTIASGEPTSTPTT EAVE, SEQ ID NO: 4).
  • the pair of milk epitopes are alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and betalac-43 (EVDDEALEKFDKA LKALPMH, SEQ ID NO: 5). In some embodiments, the pair of milk epitopes are alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and betalac-44 (DEALEKFDKALKALPMH IRL, SEQ ID NO: 6). In some embodiments, the pair of milk epitopes are alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and betalac-44 (DEALEKFDKALK ALPMHIRL, SEQ ID NO: 6).
  • the pair of milk epitopes are alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and alphas2-13 (STFCKEVVRNANEEE YSIGS, SEQ ID NO: 3).
  • any one or more of the milk epitopes described herein can be present on a solid support, such as a bead.
  • the present disclosure also provides compositions comprising any one of more (or pairs thereof) of the milk epitopes present on a solid support, such as a bead.
  • An antibody reactivity above a threshold indicates the subject has a baked milk allergic milk phenotype.
  • An antibody reactivity at or below the threshold indicates the subject does not have a baked milk allergic milk phenotype.
  • the threshold can be an antibody reactivity level known to be associated with a subject (or control population) that does not have a baked milk allergic milk phenoty pe (i.e., a control polulation).
  • the present disclosure provides methods of predicting sustained unresponsiveness to milk allergy oral immunotherapy using epitope-specific IgE antibody profiling.
  • the present disclosure provides methods of determining prior to initiating oral immunotherapy (OIT) in a subject whether the subject will experience sustained unresponsiveness (SU) after completion of the OIT.
  • the methods comprise determining the level of antibody reactivity in a sample of blood obtained from the subject to alphas2-10 (INPSKENL CSTFCKEVVRNA, SEQ ID NO: 1) or alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3), or a combination thereof.
  • a high antibody reactivity indicates the subject has a low chance of achieving SU.
  • a medium antibody reactivity indicates the subject has a medium chance of achieving SU.
  • a low antibody reactivity indicates the subject has a high chance of achieving SU.
  • the sample obtained from the subject can be any sample whereby antibody reactivity to milk peptides can be detected and measures.
  • the sample is blood.
  • the sample is serum.
  • Determining the level of antibody reactivity can be carried out by any assay that measures the level of reactivity' between an antibody in a subject to a milk peptide.
  • the assay is a bead-based epitope assay (BBEA).
  • the milk epitope can be alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) or alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3), or a combination thereof.
  • the level of reactivity is determined between an antibody and alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1).
  • the level of reactivity' is determined between an antibody and alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3). In some embodiments, the level of reactivity is determined between a combination of alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) and alphas2-13 (STFCKEVV RNANEEEYSIGS, SEQ ID NO: 3).
  • any one or more of the milk epitopes described herein can be present on a solid support, such as a bead.
  • the present disclosure also provides compositions comprising any one of more (or pairs thereof) of the milk epitopes present on a solid support, such as a bead.
  • a high antibody reactivity in some embodiments, is greater than 128 Net Median Fluorescent Intensity (NetMFI) and indicates the subject has a low chance of achieving SU.
  • NetMFI levels are subject to many laboratory conditions (e.g., antibody bead concentrations, dilution factors, reagent lots. etc.). It is the relative amounts that should be consistent. These values are the values used, for example, for this particular embodiment in Luminex Machine’s units.
  • a low chance of achieving SU is less than 30%, less than 25%, less than 20%, less than 15%. or less than 10% chance of achieving SU.
  • a low chance of achieving SU is 21%.
  • a medium antibody reactivity in some embodiments, is from 8 to 128 NetMFI and indicates the subject has a medium chance of achieving SU.
  • a medium chance of achieving SU is from about 31 % to about 69%, or from about 40% to about 60%, or from about 45% to about 55% chance of achieving SU.
  • a medium chance of achieving SU is 44%.
  • a low antibody reactivity in some embodiments, is less than 8 NetMFI and indicates the subject has a high chance of achieving SU.
  • a high chance of achieving SU is at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% chance of achieving SU. In some embodiments, a high chance of achieving SU is 80%.
  • OIT when the subject has a low antibody reactivity to alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) or alphas2-13 (STFCKEVVRNANEEE YSIGS. SEQ ID NO: 3), or a combination thereof, OIT can be administered to the subject. In some embodiments, when the subject has a high antibody reactivity to alphas2-10 (INPSKEN LCSTFCKEVVRNA, SEQ ID NO: 1) or alphas2-13 (STFCKEVVRNANEEEYSIGS, SEQ ID NO: 3), or a combination thereof, OIT may not be administered to the subject.
  • the present disclosure provides methods of determining a milk allergy threshold amount for a subject, whereby a subject with milk allergy can be stratified into low and high tolerance groups.
  • the low tolerance subject cannot consumer much milk before a reaction occurs, whereas the high tolerance subject can consume more milk. This allows for better day-to- day diet management than strict avoidance. It also allows for better clinical management, for example, whether to use Milk O1T for those with low tolerance and/or at which amount of milk to begin an OFC.
  • the present disclosure provides methods of determining a milk allergy’ threshold amount for a subject.
  • the methods comprise determining the level of antibody reactivity in a sample of blood obtained from the subject to a combination of: i) betacas-33 (KVKEAMAPKH KEMPFPKYPV, SEQ ID NO: 7) and betacas-48 (SWMHQPHQPLPPTVMFPPQS, SEQ ID NO: 8); ii) alphasl-35 (KYKVPQLEIVPNSAEERLHS, SEQ ID NO: 9) and alphas2-26 (KHYQ KALNEINQFYQKFPQY, SEQ ID NO: 10); or iii) alphal-54 (PSGAWYYVPLGTQYTDAPSF, SEQ ID NO: 11) and alphasl-55 (AWYYVPLGTQYTDAPSFSDI, SEQ ID NO: 12).
  • Antibody reactivity that is greater than a particular threshold indicates that the subject has a low tolerance to milk.
  • the sample obtained from the subj ect can be any sample whereby antibody reactivity to milk peptides can be detected and measures.
  • the sample is blood.
  • the sample is serum.
  • Determining the level of antibody reactivity can be carried out by any assay that measures the level of reactivity' between an antibody in a subj ect to a milk peptide.
  • the assay is a bead-based epitope assay (BBEA).
  • the level of antibody reactivity determined in a sample of blood obtained from the subject can be to a combination of betacas-33 (KVKEAMAPKHKEMPFPK YPV, SEQ ID NO: 7) and betacas-48 (SWMHQPHQPLPPTVMFPPQS, SEQ ID NO: 8).
  • the level of antibody reactivity determined in a sample of blood obtained from the subject can be to a combination of alphasl-35 (KYKVPQLEIVPNSAEERLHS. SEQ ID NO: 9) and alphas2-26 (KHYQKALNEINQFYQKFPQY, SEQ ID NO: 10).
  • the level of antibody reactivity 7 determined in a sample of blood obtained from the subject can be to a combination of alphal-54 (PSGAWYYVPLGTQYTDAPSF, SEQ ID NO: 11) and alphasl-55 (AWYYVPLGTQYTDAPSFSDI. SEQ ID NO: 12).
  • Antibody reactivity ratio is mapped to probability of tolerance that is greater than a particular threshold indicates that the subject has a low tolerance to milk. Antibody 7 reactivity' that is less than a particular threshold indicates that the subject has a high tolerance to milk.
  • the ratio of antibody binding to the “epitope’’ versus antibody binding to the “epitope normalizer” is calculated to produce a ratio score for a subject’s sample.
  • a database of ratio scores with their corresponding tolerated dosing is generated. Thresholds are determined to segregate the sample populations into two or more populations.
  • a single threshold value can be selected to split the database of samples into two distinct groups “low milk tolerance group” and “high milk tolerance group.”
  • alphal-54 PSGAWYYVPLGTQYTDAPSF, SEQ ID NO: 11
  • alphasl-55 AYYVPLGTQYTDAPSFSDI, SEQ ID NO: 12
  • a threshold value of 1.0 split the groups into clinically relevant populations.
  • alphasl-35 KYKVPQLEIVPNSAEERLHS, SEQ ID NO: 9
  • alphas2-26 KHYQKALNEINQFYQKFPQY, SEQ ID NO: 10
  • the subject can be stratified as having a low tolerance to milk.
  • Such subjects have about a 33% to 43% chance of tolerating 20 mg of milk, about a 10% to 15% chance of tolerating 100 mg of milk, and about a 0% chance of tolerating 300 mg or greater of milk.
  • such subjects have about a 38% chance of tolerating 20 mg of milk, about a 13% chance of tolerating 100 mg of milk, and about a 0% chance of tolerating 300 mg or greater of milk.
  • the subject can be stratified as having a high tolerance to milk.
  • Such subjects have about a 66% to 76% chance of tolerating 20 mg of milk, about a 59% to 69% chance of tolerating 100 mg of milk, about a 10% to 18% chance of tolerating 300 mg of milk, and about a 5% to 9% chance of tolerating 1500 mg of milk.
  • such subjects have about a 71% chance of tolerating 20 mg of milk, about a 64% chance of tolerating 100 mg of milk, about a 14% chance of tolerating 300 mg of milk, and about a 7% chance of tolerating 1500 mg of milk.
  • Example 1 Phenotyping of Baked vs. Non-Baked Milk Allergic Subjects using Epitope- Specific IgE Antibody Profiling
  • a phenotype test is described that differentiates baked milk allergic patients from those who are not baked milk allergic.
  • subjects from a Turkish Milk study where analyzed used the BBEA assay for milk protein allergy epitopes.
  • ses-IgE antibodies were quantified in blood samples using a bead-based epitope assay spanning milk protein allergens.
  • An optimal pair of ses-IgEs antibodies that phenotype baked milk allergy was determined using regression on 16 baked milk allergic subjects vs. 23 baked milk tolerant subjects.
  • Baked milk allergy status was established by oral food challenge and subjects ranged in age from 0.3 to 12 years of age. Cross validation was performed to establish classification performance.
  • Table 1 Top performing epitope pairs in logistic regression
  • Epitope alphas2-10 (reacting to IgE) appears in the majority of top pairings. Furthermore, when alphas2-10 is combined with an epitope (alphas2-13, IgE reactivity) that overlaps with alphas2- 10 strong separation (AUC 85%) is observed indicated that this is a dominant epitope region for the identification of phenotype. Of all pairs of ses-IgE antibodies, a pair binding two epitopes on the alpha S2 casein milk protein allergen were identified with a median cross validated AUC (area under the ROC curve) of 95%. Furthermore, these two epitopes, each of length 20 amino acids, overlap sharing 11 amino acids in common.
  • FIG. 1 shows representative results of alphas2-10 (IgE reactivity) in combination with alphas2-13 (IgE reactivity) by logistic regression giving a fitness score.
  • On the left is a boxplot of baked milk allergic vs. whole milk (i.e. milk allergic but not baked milk allergic) subjects in the Vietnamese milk study and their stratification by optimal fitness score.
  • On the right is an AUCROC for the same epitope pairing demonstrating an AUC of 95% and optimal sensitivity and specificity of 91% and 94%, respectively.
  • Figure 3 shows stratification of patients by alphas2-10 (IgE reactivity) alone for the cohorts of Baked Milk Allergic and WholeMilk (milk allergic but not baked milk allergic). Another cohort, Outgrown (subjects who outgrew their milk allergy) were included as a reference. This boxplot demonstrates the ability of alphas2-10 to stratify patients by phenotype.
  • Example 2 Predicting Sustained Unresponsiveness (SU) to Milk Allergy Oral Immunotherapy using Epitope-Specific IgE Antibody Profiling
  • ses-IgE profiling It was sought to determine whether sequential (linear) epitope-specific IgE (ses-IgE) profiling can predict if SU can be achieved before OIT is initiated. Specifically, a previously identified ses-IgE antibody that binds to an epitope (named alphas2-10) on the alpha S2 casein milk protein allergen was assessed. This ses-IgE antibody was found to be highly reactive in baked milk allergic patients vs. baked milk tolerant patients.
  • the BBEA method using epitopes from milk allerg)’ proteins was applied to 47 subjects who underwent Milk OIT with a follow up assessment after the cessation of OIT.
  • the BBEA analysis was performed on samples collected from the subjects before the initiation of OIT so that the results could potentially predict SU. Both epitope reactivity to IgE and IgG4 was collected in the analysis.
  • the follow up assessment was an OFC to determine if milk allergy desensitization was sustained or not.
  • the alphas2-10 ses-IgE antibody was profiled on blood samples, taken prior to initiation of milk OIT, from 47 subjects of ages 7 to 32 years. These subjects underwent milk OIT therapy for a period of 26 months with sustained unresponsiveness assessed by oral food challenge 2 months after cessation of treatment.
  • the epitope reactivity' to IgE was binned into three levels (high, medium, low) and the rate of sustained unresponsiveness of patients in each level determined.
  • a single epitope, alphas2-10 (INPSKENLCSTFCKEVVRNA, SEQ ID NO: 1) (IgE reactivity) was measured using the BBEA method on blood drawn before treatment.
  • Table 2 shows the predictive power of this epitope at low', medium, and high levels of epitope reactivity to IgE, for predicting SU.
  • Table 2 Percentage of patients achieving SU as determined by levels of alphas2-10 reactivity to IgE
  • low alphas2-10 reactivity to IgE indicated that there was an 80% chance of achieving SU, and so, an indicator that OIT would very likely provide benefit for the patient.
  • a high alphas2-10 reactivity to IgE indicated that there was only a 21% chance of achieving SU, and so, an indicator that OIT would very likely not provide benefit for the patient.
  • Table 3 Percentage of patients achieving SU as determined by levels of alphas2-10 and alphas2-13 reactivity 7 to IgE
  • low reactivity with IgE corresponded to high probability (77%) of SU whereas high reactivity to IgE corresponded to low probability (31%) of SU.
  • the BBEA method using epitopes from milk allergy’ proteins was applied to 38 subjects with milk allergy with highest milk tolerance levels determined by standardize (PRACTALL) OFC. Both epitope reactivity' to IgE and IgG4 was collected in the analysis.
  • Table 4 presents three of the highest performing pairs of epitopes in terms of Pearson and Spearman correlation to OFC-determine milk tolerance levels. The p-values of these correlations are all highly significant.
  • Betacas-33 KVKEAMAPKHKEMPFPKYPV, SEQ ID NO: 7; Alphasl-35: KYKV PQLEIVPNSAEERLHS, SEQ ID NO: 9; Alphal-54: PSGAWYYVPLGTQYTDAPSF, SEQ ID NO: 11; Betacas-48: SWMHQPHQPLPPTVMFPPQS, SEQ ID NO: 8; Alphas2-26: KHYQKAL NEINQFYQKFPQY, SEQ ID NO: 10; and Alphasl-55: AWYYVPLGTQYTDAPSFSDL SEQ ID NO: 12.
  • the 38 samples were split into a low and high milk tolerance group (see, Figure 4 and Figure 5).
  • the tolerance profile for the group was represented by the percentage of patients that can tolerate at least 0 mg, 20 mg, 100 mg, 300 mg, and 1500 mg of milk allergen (Successfully Consumed Doses or SCD). For example, only 38% of subjects in the low tolerance group can tolerate 20 mg of milk whereas 71% of subjects in the high tolerance group can tolerate 20 mg of milk.

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Abstract

L'invention concerne des procédés de détermination du phénotype laitier d'un sujet, des procédés pour déterminer, avant de lancer une immunothérapie orale (ITO) chez un sujet, si le sujet subira une tolérance soutenue (SU) après l'achèvement de l'ITO, et des procédés de détermination d'une quantité de seuil d'allergie au lait pour un sujet.
EP24745049.7A 2023-01-16 2024-01-16 Dosages pour déterminer des allergies au lait Pending EP4652461A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363439238P 2023-01-16 2023-01-16
PCT/US2024/011582 WO2024155569A2 (fr) 2023-01-16 2024-01-16 Dosages pour déterminer des allergies au lait

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EP4652461A2 true EP4652461A2 (fr) 2025-11-26

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