阅读说明：本技术 对隐形眼镜不适易感的隐形眼镜佩戴者的识别 (Identification of contact lens wearer for susceptibility to contact lens discomfort ) 是由 劳拉·伊丽莎白·唐尼 大卫·查尔斯·杰克逊 阿尔吉斯·约纳斯·维恩格里斯 南希·J·基尔 茵 于 2019-03-06 设计创作，主要内容包括：描述用以识别对隐形眼镜不适易感的隐形眼镜佩戴者的方法和装置。所述方法和装置涉及自人获得泪膜样本和测定存在于所述泪膜样本中的白介素-17A的量。(Methods and devices are described to identify contact lens wearers who are not comfortable with contact lenses. The methods and devices involve obtaining a tear film sample from a human and determining the amount of interleukin-17A present in the tear film sample.)

1. A method of determining a patient's susceptibility to wearing a symptomatic contact lens, the method comprising:

a) optionally determining a baseline concentration of interleukin-17A (IL-17A) in a sample of unstimulated tear fluid from the patient;

b) delivering a stimulus to sensory neurons of the patient's cornea to produce a stimulated tear sample in the patient;

c) determining the concentration of IL-17A in the stimulated tear sample; and

d) classifying the patient as being susceptible to symptomatic contact lens wear if

i) The concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with susceptibility to symptomatic contact lens wear, and/or

ii) the concentration of IL-17A in the stimulated tear sample is greater than the baseline concentration of IL-17A.

2. A method of determining a contact lens wearer for whom a patient is predisposed to being asymptomatic, the method comprising:

a) determining a baseline concentration of IL-17A in an unstimulated tear sample from the patient;

b) delivering a stimulus to sensory neurons of the patient's cornea to produce a stimulated tear sample in the patient;

c) determining the concentration of IL-17A in the stimulated tear sample; and

d) classifying the patient as being prone to asymptomatic contact lens wearers if the concentration of IL-17A in the stimulated tear sample is less than 150% of the baseline concentration of IL-17A.

3. The method of claim 1, wherein the baseline concentration of IL-17A is determined in an unstimulated tear sample from the patient, and the patient is classified as being susceptible to a symptomatic contact lens if the post-stimulation concentration of IL-17A is greater than the baseline concentration of IL-17A.

4. The method of claim 1 or 2, wherein the stimulus is a mechanical stimulus delivered by contact lens wear.

5. The method of claim 1 or 2, wherein the IL-17A concentration is measured using an immunochromatographic assay.

6. A kit for determining a susceptibility of a patient to symptomatic contact lens wear, the kit comprising an antibody that specifically binds to IL-17A, wherein the kit is used to determine a high risk of symptomatic contact lens wear if the concentration of IL-17A in a sample of stimulated tear fluid from the patient is above a predetermined cutoff value associated with symptomatic contact lens wear.

7. The kit of claim 6, wherein the cut-off value is at least 75 pg/ml.

8. The kit of claim 6, comprising a lateral flow chromatography test strip.

9. The kit of claim 8, comprising a sample coating area; a reagent region comprising an antibody conjugate comprising a detectable label bound to a first capture antibody that specifically binds IL-17A, wherein the antibody conjugate is in fluid communication with the sample coated region; and a test region comprising a second capture antibody that specifically binds IL-17A and is in fluid communication with the reagent region.

10. A kit for determining a susceptibility to asymptomatic contact lens wear in a patient, the kit comprising an antibody that specifically binds to IL-17A, wherein the kit is used to determine a susceptibility to asymptomatic contact lens wear if the concentration of IL-17A in a stimulated tear sample of the patient is lower than the concentration of IL-17A in an unstimulated tear sample of the patient.

11. The kit of claim 10, comprising a lateral flow chromatography test strip comprising:

a) a first sample coating region for coating the unstimulated tear sample;

b) a second sample coating region for coating the stimulated tear sample;

c) a first reagent zone in fluid communication with the first sample coated zone,

d) a second reagent zone in fluid communication with the second sample application zone,

e) a first test zone in fluid communication with the first reagent zone, and

f) a second test zone in fluid communication with the second reagent zone,

wherein each of the first and second reagent regions comprises an antibody conjugate comprising a detectable label bound to a first capture antibody that specifically binds IL-17A, and each of the first and second test regions comprises a second capture antibody that specifically binds IL-17A, and wherein a lower concentration of IL-17A in the stimulated tear sample of the patient is determined by a lower concentration of the detectable label in the first reagent region compared to the second reagent region after the unstimulated and stimulated tear samples are applied to the first and second sample-coated regions, respectively.

12. The kit of claim 6 or 10, further comprising a tear collection device.

13. Use of an antibody that specifically binds IL-17A for the manufacture of a device for diagnosing susceptibility of a patient to symptomatic contact lens wear.

14. The use of claim 13, wherein the device comprises a lateral flow chromatography test strip.

15. A method of selecting a treatment for a patient in need of vision correction, the method comprising:

a) optionally determining a baseline concentration of interleukin-17A (IL-17A) in an unstimulated tear sample from the patient;

b) delivering a stimulus to sensory neurons of the patient's cornea to produce a stimulated tear sample in the patient;

c) collecting the stimulated tear sample;

d) determining the concentration of IL-17A in the stimulated tear sample; and

e) prescribing a treatment to the patient to prevent or reduce discomfort associated with contact lens wear when

i) The concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to a symptom, and/or

ii) the concentration of said IL-17A in said stimulated tear sample is greater than the baseline concentration of said IL-17A.

16. The method of claim 15, wherein the concentration of IL-17A in the stimulated tear sample is determined by contacting the stimulated tear sample with an antibody that specifically binds IL-17A and detecting the antibody that has bound to IL-17A.

17. The method of claim 16, wherein the antibody that specifically binds IL-17A is a component of an immunochromatographic assay.

18. The method of claim 15, wherein the patient is prescribed a contact lens for vision correction and the treatment to reduce discomfort associated with contact lens wear is selected from the group consisting of administration of a neurological agent, an anti-inflammatory agent, a moisturizing eye drop, and combinations thereof.

19. The method of claim 15, wherein the treatment to prevent or reduce discomfort associated with contact lens wear comprises prescribing the patient with an ophthalmic lens for vision correction.

20. A method of treating a patient in need of vision correction, the method comprising:

a) optionally determining a baseline concentration of interleukin-17A (IL-17A) in a sample of unstimulated tear fluid from the patient;

b) delivering a stimulus to sensory neurons of the patient's cornea to produce a stimulated tear sample in the patient;

c) collecting the stimulated tear sample;

d) determining the concentration of IL-17A in the stimulated tear sample; and

e) providing a therapeutic prescription to the patient to prevent or reduce discomfort associated with contact lens wear when

i) The concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to a symptom, and/or

ii) the concentration of said IL-17A in said stimulated tear sample is greater than the baseline concentration of said IL-17A.

21. The method of claim 20, wherein the concentration of IL-17A in the stimulated tear sample is determined by contacting the stimulated tear sample with an antibody that specifically binds IL-17A and detecting the antibody that has bound to IL-17A.

22. The method of claim 21, wherein the antibody that specifically binds IL-17A is a component of an immunochromatographic assay.

23. The method of claim 20, wherein the patient is prescribed a contact lens for vision correction and the treatment to reduce discomfort associated with contact lens wear is selected from the group consisting of administration of a neurological agent, an anti-inflammatory agent, a moisturizing eye drop, and combinations thereof.

24. The method of claim 20, wherein the treatment to prevent or reduce discomfort associated with contact lens wear comprises prescribing the patient with an ophthalmic lens for vision correction.

25. The method of claim 20, wherein the prescription is a contact lens for vision correction and administration of a neurological agent, an anti-inflammatory agent, a moisturizing eye drop, or any combination thereof.

26. The method of claim 20, wherein the prescription is an ophthalmic lens for vision correction.

27. A method of treating a patient in need of vision correction, the method comprising:

a) optionally determining a baseline concentration of interleukin-17A (IL-17A) in an unstimulated tear sample from the patient;

b) delivering a stimulus to sensory neurons of the patient's cornea to produce a stimulated tear sample in the patient;

c) collecting the stimulated tear sample;

d) determining the concentration of IL-17A in said stimulated tear sample, and whether said concentration is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to the condition and/or whether the concentration of IL-17A in said stimulated tear sample is above said baseline concentration of IL-17A, and if so, then

e) Providing the open contact lens to the patient for vision correction and administration of a neuropharmaceutical, an anti-inflammatory, a moisturizing eye drop, or any combination thereof or providing the open contact lens to the patient for vision correction.

Technical Field

The field of the invention relates to methods and devices for identifying contact lens wearers susceptible to contact lens discomfort.

Background

Inflammation is a complex nonspecific tissue reaction triggered by exposure to potentially harmful stimuli and is several including dry eye^1,2And conjunctival relaxation³Eye sensitivity^4,5And blepharitis⁴Is characteristic of an ocular surface pathology. In these clinical manifestations, the anterior ocular response is typically characterized by typical symptoms of inflammation, including redness, pain, swelling, heat, and loss of normal function. These clinical symptoms are accompanied by a focus on the surface cells such as human leukocyte antigens (HLA-DR)⁶And intercellular adhesion molecule-1 (ICAM-1)⁷Of an inflammatory biomarker. In addition, there are changes in tear film composition, including upregulation of pro-inflammatory interleukins^1,8,9Changes in tear lipid mediators¹⁰And increased tear protease activity (e.g., metalloproteases, MMP-9)^3,4,11And MMP-2¹²)。

Although uncomplicated contact lens wear is not accompanied by these typical symptoms of inflammation, it remains controversial that the inflammation experienced by some contact lens wearers causes an adverse reaction. Contact lens discomfort is a multifactorial condition characterized by "intermittent or persistent adverse ocular sensations associated with contact lens wear²³. In the united states, approximately three million or one out of six contact lens wearers abandon contact lenses each year; discomfort being the main cause of the stoppage²⁴. Currently, the etiology of this malaise is not clear. Notably, the symptoms (e.g., ocular irritation, burning, stinging and pain) reported by patients experiencing symptomatic eyewear wear are very similar to symptomology associated with dry eye, which is believed to involve inflammatory coverage²⁵。

Part of the clinical data supports the presence of a low-grade subclinical anterior ocular inflammatory response during contact lens wear, which may be exaggerated by persons experiencing discomfort²⁶. Contact lens wear changes the relative content of a range of tear film mediators^27-31. However, in contrast to dry eye disease in which tear-stimulating inflammatory cytokine levels are elevated and disease processes are implicated^1,2The relationship between ocular discomfort and upregulation of specific inflammatory mediators has not been clearly demonstrated^32,33. Changes in major tear film mediators, including the complement cascade, kinin cascade and histamine, do not appear to correlate with comfort³⁴. The effects of neurokinin growth factors have been proposed³⁵Which may induce hyperalgesia and mast cell degranulation³⁶And the action of prolactin-inducing proteins that regulate water transport in the lacrimal gland³⁷. Other potential molecular candidates include decomposed lipids, leukotriene-B4 and peroxidation products, and enzymes, i.e., secreted phospholipase-A2³⁴。

It would be desirable to identify contact lens wearers or prospective contact lens wearers who may be prone to contact lens discomfort so that proactive steps can be taken to improve the contact lens wearing experience of such patients.

Disclosure of Invention

As disclosed herein, the present invention is based on the following findings: contact lens wearers, or prospective contact lens wearers, can be differentiated by the amount of interleukin-17A (IL-17A) present in the tear film of the wearer. Using this discovery and the present methods and devices disclosed herein, it is possible to improve contact lens products by imparting a vision correction solution suitable for either symptomatic or asymptomatic contact lens wearers.

In one aspect, the invention provides a method of determining contact lens wear of a patient susceptible to a condition. The method includes delivering a stimulus to corneal sensory neurons of a patient to produce a stimulated tear sample in the patient. In the method, the concentration of IL-17A in the stimulated tear sample is determined. The method may also comprise the optional step of determining a baseline concentration of IL-17A in the unstimulated tear sample from the patient. Classifying the patient as being susceptible to symptomatic contact lens wear if (i) the concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to the symptomatic condition, and/or (ii) the concentration of IL-17A in the stimulated tear sample is above a baseline concentration of IL-17A.

In another aspect, the invention provides a method of determining a predisposition of a patient to an asymptomatic contact lens wearer. The method includes the step of determining a baseline concentration of IL-17A in a sample of unstimulated tears in the patient. The method includes the additional steps of delivering a stimulus to corneal sensory neurons of the patient to produce a stimulated tear sample in the patient and determining the concentration of IL-17A in the stimulated tear sample. If the concentration of IL-17A in the stimulated tear sample is less than 150% of the baseline concentration of IL-17A, the patient is classified as susceptible to being an asymptomatic contact lens wearer.

In another aspect of the invention, the invention provides a kit.

For example, a kit for determining a patient's susceptibility to symptomatic contact lens wear comprises an antibody that specifically binds to IL-17A. Using the kit, a high risk symptomatic contact lens wear is determined using the kit if the concentration of IL-17A in the stimulated tear sample of the patient is above a predetermined cutoff value associated with symptomatic contact lens wear.

As another example, a kit for determining that a patient is predisposed to asymptomatic contact lens wear comprises an antibody that specifically binds to IL-17A. Using this kit, a patient's propensity for asymptomatic contact lens wear is determined using the kit if the concentration of IL-17A in a sample of stimulated tear fluid is lower than the concentration of IL-17A in a sample of unstimulated tear fluid.

In another aspect, the invention provides the use of an antibody that specifically binds IL-17A in the manufacture of a device for diagnosing contact lens wear in a patient susceptible to a condition.

Additional aspects and embodiments of the present methods and apparatus will be apparent from the ensuing description, examples, drawings, and claims. As can be appreciated from the foregoing and following descriptions, each of the features described herein, and each of two or more of such features, is included within the scope of the present invention provided that the features included in such a combination are not mutually inconsistent. Furthermore, any feature or combination of features may be specifically excluded from any embodiment of the present invention.

Drawings

FIG. 1 depicts an exemplary immunoassay device for detecting IL-17A in a tear sample.

Detailed Description

Immunological and clinical characterization of ocular inflammatory responses in symptomatic soft contact lens wearers as compared to asymptomatic wearers is undertaken in an effort to gain insight into the nature of the inflammatory response that occurs in people experiencing contact lens discomfort. This work led to the present invention relating to methods, devices and kits that address the needs that exist for: improving the contact lens wearing experience for patients who may be susceptible to contact lens discomfort. Disclosed herein are methods, devices, and kits for determining contact lens wear of a patient susceptible to a condition. Symptomatic contact lens wear is generally characterized by lens wearers experiencing discomfort when wearing the lens continuously for 3 hours or more. In one method, a tear sample is collected from a patient whose cornea and/or conjunctiva has not been subjected to any significant mechanical stimulation for a period of time, such as at least 30 minutes, 1 hour, 2 hours, or 4 hours, prior to the collection of the sample. In some methods, the patient has not worn a contact lens or has not experienced any other significant mechanical stimulus for at least 12 hours or 16 hours prior to collecting the sample. Throughout this disclosure, when a qualifier precedes a first value to provide a series of values, the qualifier is intended to implicitly precede each of the successive values unless the context dictates otherwise. Thus, for example, in the above schedule, the qualifier "at least" implicitly precedes each specified period. For simplicity, as used herein, reference to "eye" refers to the cornea and/or conjunctiva, unless otherwise specified. The collected tear sample is referred to herein as an "unstimulated tear sample". A significant mechanical stimulus is delivered to the patient's eye and a "stimulated tear sample" is taken either before or after the unstimulated tear sample is taken. The concentration of interleukin-17A (IL-17A) in each of the tear samples is determined, and the patient is identified as being susceptible to symptomatic contact lens wear if the concentration of IL-17A in the stimulated tear sample is higher than the concentration of IL-17A in the unstimulated tear sample, which is referred to herein as the "baseline concentration of IL-17A.

In a modification of the above method, it is optional to collect a sample of unstimulated tears. Identifying the patient as susceptible to symptomatic contact lens wear if the concentration of stimulated tear sample IL-17A is at or above a predetermined cutoff value associated with susceptible to symptomatic contact lens wear. Such methods for determining contact lens wear that a patient is susceptible to a condition are described in more detail below. In some examples, a non-stimulated tear sample is taken, and if the concentration of IL-17A in the stimulated tear sample is: 1) at or above a cutoff value predetermined to be associated with a contact lens wear susceptible to a symptom, and 2) above a baseline concentration of IL-17A, then the patient is identified as being susceptible to a symptom.

Also disclosed herein is a method of determining a patient's predisposition to asymptomatic contact lens wear. Asymptomatic contact lens wear is generally characterized by lens wearers experiencing little to no discomfort after at least 8 hours of continuous contact lens wear. The method comprises collecting a stimulated tear sample and a non-stimulated tear sample from the patient as described above and in more detail below. The concentration of IL-17A in each tear sample is determined, and the patient is identified as being predisposed to asymptomatic contact lens wear if the concentration of IL-17A in the stimulated tear sample is below a baseline concentration of IL-17A or below a baseline concentration of IL-17A by a specified percentage. For example, if the concentration of IL-17A in a stimulated tear sample is 200% or 150% below the baseline concentration of IL-17A, the patient may be identified as being predisposed to asymptomatic contact lens wear.

Further disclosed herein is a method of selecting a treatment for a patient in need of vision correction, wherein the method comprises optionally determining a baseline concentration of interleukin-17A (IL-17A) in a sample of unstimulated tear fluid from the patient; delivering a stimulus to sensory neurons of a cornea of a patient to produce a stimulated tear sample in the patient; collecting a stimulated tear sample; determining the concentration of IL-17A in the stimulated tear sample; and prescribing treatment to the patient to prevent or reduce discomfort associated with contact lens wear when the concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to the condition and/or the concentration of IL-17A in the stimulated tear sample is above a baseline concentration of IL-17A.

Also disclosed herein is a method to treat a patient in need of vision correction, wherein the method comprises optionally determining a baseline concentration of interleukin-17A (IL-17A) in an unstimulated tear sample from the patient; delivering a stimulus to sensory neurons of a cornea of a patient to produce a stimulated tear sample in the patient; collecting a stimulated tear sample; determining whether the concentration and concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to the condition and/or whether the concentration of IL-17A in the stimulated tear sample is above a baseline concentration of IL-17A, and if so, then providing the patient with an open contact lens for vision correction and administering a neuropharmaceutical, an anti-inflammatory agent, a moisturizing eye drop, or any combination thereof or providing the patient with an open ophthalmic lens for vision correction.

Further disclosed herein is a method of treating a patient in need of vision correction, wherein the method comprises optionally determining a baseline concentration of interleukin-17A (IL-17A) in an unstimulated tear sample from the patient; delivering a stimulus to sensory neurons of a cornea of a patient to produce a stimulated tear sample in the patient; collecting a stimulated tear sample; determining the concentration of IL-17A in the stimulated tear sample; and providing a treatment prescription to the patient to prevent or reduce discomfort associated with contact lens wear when the concentration of IL-17A in the stimulated tear sample is at or above a cutoff value predetermined to be associated with susceptibility to symptomatic contact lens wear and/or the concentration of IL-17A in the stimulated tear sample is above a baseline concentration of IL-17A.

In any of the methods of the invention, the concentration of IL-17A in the stimulated tear sample can be determined by contacting the stimulated tear sample with an antibody that specifically binds IL-17A and detecting the antibody that has bound to IL-17A. As an option, antibodies that specifically bind IL-17A may be a component of an immunochromatographic assay.

In any of the methods of the present invention, the treatment for prescribing or providing a contact lens to a patient for vision correction, and/or for reducing discomfort associated with contact lens wear, may be selected from administration of a neurological agent, an anti-inflammatory agent, a moist eye drop, or any combination thereof.

In any of the methods of the invention, the treatment for preventing or reducing wear associated with contact lenses may or comprises prescribing to a patient an ophthalmic lens for vision correction.

In any of the methods of the present invention, the prescription can be a contact lens for vision correction and/or administration of a neurological agent, an anti-inflammatory agent, a moisturizing eye drop, or any combination thereof.

In any of the methods of the present invention, the prescription may be an ophthalmic lens for vision correction.

The following details apply to the methods summarized above, unless the context dictates otherwise. Throughout this disclosure, reference to "an example" or "a particular example" or similar phrase is intended to introduce a feature of the method, apparatus, etc., that may be combined with the previously described or subsequently described examples (i.e., features), unless the particular combination of features is exclusive of one another or if the context dictates otherwise. As used herein, tears collected from a patient are considered "unstimulated" if the patient's eye has not experienced significant mechanical stimulation prior to collection of the tear sample. As used herein, significant mechanical stimulation refers to mechanical forces on the eye that can potentially cause the membrane to deform to activate the multiple modes and/or mechanoreceptors. In some examples, the patient has not experienced significant mechanical stimulation for at least 30 minutes, 1 hour, 2 hours, or 4 hours prior to collecting the unstimulated tear sample. Examples of significant mechanical stimuli include contact lens wear, exposure to windy conditions, rubbing the eye, exposure to significant contamination, chemical exposure, and other stimuli that may activate one or more sensory neurons. In addition, conditions such as allergy and conjunctivitis can also activate receptors, and thereby preferably delay the collection of unstimulated tear samples until after such conditions have cleared. In one example, the patient does not wear a contact lens for at least 12 hours, 16 hours, 24 hours, or 48 hours prior to collecting the unstimulated tear sample.

Tear samples may be collected using any suitable method that permits measurement of IL-17A in the collected sample. In one example, tear samples are collected by microcapillaries. In another example, tear samples are collected using strips of absorbent material. Suitable materials for collecting tear fluid samples are known in the art (see, e.g., Hiya (Sia) et al, J Opthalmol Clin Res (2016)3: 048). Conveniently, the tear collection device may be part of a test kit for measuring IL-17A in a tear sample as described in more detail below. During the collection of the tear fluid sample, care was taken to avoid any irritation to the eye to avoid reflex tearing so that only basal tears were collected. Tears of one or both eyes may be collected. When collecting tears from both eyes, the collected tears can be combined to produce a single sample. Alternatively, the concentration of IL-17A in two collected tear samples (i.e., a sample from the left eye and a sample from the right eye) can be measured. In one example, a first collected tear sample, typically an unstimulated tear sample, is stored in a refrigerator until a second tear sample (typically a stimulated tear sample) is collected so that the IL-17A concentration in both tear samples can be tested simultaneously. In another example, the concentration of IL-17A in the collected first tear sample can be tested immediately after collection, such as within 60 minutes, within 30 minutes, or within 10 minutes.

As used herein, a "stimulated tear sample" refers to basal tears collected from a patient whose eye has undergone significant mechanical stimulation prior to collection of the tear sample. Typically, both eyes experience the same mechanical stimulus. Stimulated tear samples may be collected from one or both eyes. If collected from both eyes, tears from each eye can be combined to produce a single stimulated tear sample, or they can be tested separately for IL-17A concentration. In one example, when tear samples from each eye are tested separately, the higher of the two measured concentrations of IL-17A may be used to classify the patient as symptomatic or asymptomatic. As with the unstimulated tear sample, care was taken to avoid reflex tearing during tear collection. In one example, contact lens wear provides significant mechanical irritation to the eye. In various examples, the contact lens is worn for at least 2 hours, 4 hours, or 6 hours prior to tear sample collection. In some examples, the contact lens is removed from the patient's eye and the stimulated tear sample is immediately collected from the removed contact lens.

In some examples, when the stimulus is contact lens wear, the unstimulated tear sample and the stimulated tear sample can be collected on different days. In this example, two samples may be collected at approximately the same time of day. For example, the second sample may be collected within 120 minutes, 90 minutes, or 60 minutes of the day the first sample was collected. In some examples, the sample is collected about 2 to 6 hours after the patient has been awake. In another example, both unstimulated and stimulated tear samples may be collected on the same day. For example, an unstimulated tear sample can be collected from a patient, followed by subjecting the patient's eye to significant mechanical stimulation, such as wearing a contact lens for at least 2, 4, or 6 hours, followed by collection of a stimulated tear sample.

Stimuli other than contact lens wear may be used as mechanical stimuli for producing stimulated tear samples, with the proviso that stimulation produces a significant correlation between IL-17A concentration and CLDEQ-8 score when tested in a clinical study such as described in example 1 below.

The concentration of IL-17A in the tear sample can be determined using any suitable method. Exemplary methods are well known in the art and include cytological bead arrays, ELISA assays, lateral flow immunoassays such as immunochromatographic assays, microfluidic (e.g., "lab on a chip") immunoassays, and the like. The use of the cytological bead array is detailed in example 1 below. Kits for determining the susceptibility to symptomatic contact lens wear are further described below. The phrase "determining the concentration of IL-17A" encompasses both quantitative and/or qualitative determinations. Thus, in one example, the concentration of IL-17A in a tear sample can be measured, typically in pg/ml. In another example, the amount of IL-17A in a stimulated tear sample may be determined to be above or below a baseline IL-17A concentration. In another example, the amount of IL-17A in a stimulated tear sample may be determined to be above or below a cutoff value predetermined to be associated with a contact lens wear susceptible to a condition.

The cutoff value associated with a contact lens wear susceptible to symptoms can be predetermined in a clinical study such as that described in example 1 below. Variations in the general method used to produce the stimulated tear sample can determine the particular cut-off value selected. For example, the type of stimulus used to generate the stimulated tear sample and the duration of the stimulus are factors that may affect the concentration of IL-17A in the stimulated tear sample. Furthermore, as understood in the field of medical diagnostics, the desired specificity and sensitivity of the test will also take into account the choice of cut-off values for the method. In various examples, the cutoff value associated with a contact lens wear susceptible to a symptom is predetermined to be at least 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150pg/ml IL-17A. In some examples, the cutoff value associated with contact lens wear susceptible to a symptom is predetermined to be at least 75pg/ml, 100pg/ml, or 125pg/ml, and at most about 350pg/ml or 400 pg/ml. Throughout this disclosure, unless the context dictates otherwise, when the last value in a series of numerical values is followed by a unit of measurement, the unit of measurement is intended to implicitly follow each value in the series. Thus, in the above list, the unit pg/ml is intended to follow each of the values listed (i.e., 70pg/ml, 75pg/ml), and so forth.

In a method of determining a baseline concentration of IL-17A in an unstimulated tear sample from a patient, the patient can be classified as susceptible to symptomatic contact lens wear if the concentration of IL-17A in the stimulated tear sample is greater than the baseline concentration of IL-17A. In other examples, a patient may be classified as symptomatic and susceptible contact lens wear if the concentration of IL-17A in the stimulated tear sample is at least 125%, 150%, 175%, 200%, 225%, 250%, 275%, or 300% of the baseline concentration. The amount of increase in IL-17A concentration selected as a predictor of symptomatic contact lens wear may depend on the degree of specificity and sensitivity desired for the method and method used to produce the stimulated tear sample. In another example, a patient can be classified as a symptomatic susceptible contact lens wear if the concentration of IL-17A in the stimulated tear sample is 1) above a baseline concentration of IL-17A and 2) at or above a cutoff value associated with symptomatic susceptible contact lens wear.

The methods described herein advantageously enable eye care professionals to provide better patient care and management, which results in higher patient satisfaction and retention. An eye care professional may provide a different post-cure care schedule or recommendation for a patient determined to be susceptible to symptomatic contact lens wear than a patient determined to be prone to asymptomatic contact lens wear. For example, a patient determined to be susceptible to symptomatic contact lens wear may be prescribed more comfortable, high-quality lenses and/or ocular treatments, such as wet eye drops that promote ocular comfort, anti-inflammatory agents such as corticosteroids, or other treatments that may reduce contact lens discomfort.

As described above, any conventional method, and in particular any conventional immunoassay method, can be used to determine the concentration of IL-17A in a tear sample. It has been found that the correlation between IL-17A concentration in stimulated tear samples and susceptibility to symptomatic contact lens wear enables the design of immunoassay kits and devices specifically adapted for testing tear samples to identify patients prone to asymptomatic or symptomatic contact lens wear.

In one example, a kit for determining a patient's susceptibility to symptomatic contact lens wear comprises an antibody that specifically binds to IL-17A, wherein the kit is used to determine a high risk of symptomatic contact lens wear if the concentration of IL-17A in a sample of stimulated tear fluid from the patient is above a predetermined cutoff value associated with symptomatic contact lens wear. In various examples, the cutoff value is at least 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150pg/ml IL-17A. An exemplary kit for determining the susceptibility of a patient to the wearing of a contact lens having a symptom comprises lateral flow chromatography test strip means. Referring to fig. 1, a tear sample 11 is applied to a sample application area 12, which typically includes an absorbent material. As depicted in fig. 1, the sample application zone may be proximal to the reagent zone 13 and in fluid communication with the reagent zone 13. In other examples, the sample may be applied to the reagent zone immediately, i.e., the sample application zone and the reagent zone are in the same location of the testing device. Two such examples are considered herein as the sample application region being in fluid communication with the reagent region.

In one example, the reagent zone 13 comprises an absorbent material to which antibody conjugates are releasably bound. The antibody conjugate comprises a detectable label 14 bound to a first capture antibody 15 that specifically binds IL-17A. As used herein, the term "antibody" encompasses any suitable antibody or antibody fragment (e.g., polyclonal, monoclonal, Fab, etc.). When the reagent zone is wetted by the sample, antibody conjugate is released from the reagent zone and drawn into and through the test strip 16, which includes the test zone 17 containing the second capture antibody 18 that specifically binds IL-17A present in the sample. The second capture antibody typically binds IL-17A at a different epitope than the first capture antibody. In some examples, the first capture antibody is a monoclonal antibody and the second capture antibody is a polyclonal antibody. If a sufficiently high concentration of IL-17A is present, the labels 14 will be sufficiently concentrated in the test area 17 so that they can be detected.

After the sample and capture antibody reach the test zone, the remaining sample and antibody conjugate will continue to wick across the test strip to the control zone 20, which in one example may comprise a control antibody 21 bound to the antibody conjugate. In this example, detection of the marker 14 at the control area indicates that the test device is functioning properly. In other examples, the control zone may comprise a reagent such as an enzyme or antibody that reacts with a component normally present in the tear fluid to provide a signal indicative of the proper functioning of the test. In some examples, the lateral flow chromatography test strip tape apparatus may also include an absorbent pad 22 to absorb residual sample and/or a liquid impermeable backing or housing 23.

FIG. 1 depicts the presence of IL-17A 19 in tear sample 11. At sufficiently high concentrations of IL-17, the label at the test area 17 will be detectable. In one example, the amount of first capture antibody present in the test zone can be selected such that a label is detectable only when the concentration of IL-17A in the tear sample is equal to or above a cutoff value predetermined to be associated with symptomatic contact lens wear. In such examples, the amount of control antibody 21 present in the control zone 20 can be selected to capture an amount of conjugate antibody to provide a level of detectable signal representative of a cutoff value predetermined to be associated with symptomatic contact lens wear. In such instances, the patient is identified as being susceptible to symptomatic contact lens wear if the concentration of the label bound to the test zone is equal to or higher than the concentration of the label bound to the control zone.

A variety of detectable labels suitable for use in lateral flow chromatography test strip devices are well known in the art. In one example, the detectable label 14 is visually detectable when sufficiently focused. Visually detectable labels such as colloidal gold are particularly convenient for testing samples in the eye care practitioner's office, as no special equipment is required for label detection. In other examples, the label may be an enzyme that produces a color when a substrate for the enzyme is added to the test strip. In such examples, the kit may additionally comprise a reagent comprising a substrate. Reagents are applied to the test strip after the sample has been added and the substrate is allowed to react with the enzyme label for a sufficient amount of time before the test results are read.

It will be appreciated that alternatives to the immunoassay device illustrated by fig. 1 may be used in the practice of the present invention. As an alternative example, both the first capture antibody and the second capture antibody may be present in the reagent region. IL-17A, if present in the tear sample, forms an immune complex with both the first and second capture antibodies. In this example, the first capture antibody can comprise a detectable label and the test region can comprise a molecule that specifically binds the second capture antibody. For example, the second capture antibody can be biotinylated and the test region can comprise an avidin, streptavidin, or another biotin-binding molecule. In the examples described above, and in other examples not specifically described herein, the use of an antibody uniformly characterized as specifically binding to IL-17A for the manufacture of a device for diagnosing contact lens wear susceptible to a symptom in a patient.

Kits for determining susceptibility to symptomatic or asymptomatic contact lens wear will typically comprise a tear collection device, such as a microcapillary tube or a strip of absorbent material. In some examples, the lateral flow chromatography test strip device may be configured to accommodate a tear collection device at the sample application area. Such configurations have been previously described in the art (see, e.g., U.S. patent No. 7,723,124, also by Quidel corporation)。

The invention also provides kits for determining a patient's predisposition to asymptomatic contact lens wear, wherein the kit is used to determine a patient's predisposition to asymptomatic contact lens wear if the concentration of IL-17A in a stimulated tear sample is lower than the concentration of IL-17A in an unstimulated tear sample of the patient. In one example, a kit may comprise a device containing two lateral flow chromatography test strips, the test strips being parallel to each other and contained within a single housing. An unstimulated tear sample is applied to one of the strips and a stimulated tear sample is applied to the other strip. The housing may contain a liquid impermeable spacer between the two strips to avoid cross-contamination of the samples. Each of the test strips may contain the same components as described above, such as sample coated areas, test areas, and control areas, among others. However, in this example, if the amount of the indicia concentrated in the test area of the test strip for the stimulated tear sample is lower than the amount of the test area for the unstimulated tear sample, then it is determined that asymptomatic contact lens wear is predisposed.

Any one or more of the above kits or components thereof may be used in any of the methods described herein.

Additional aspects of the invention

The invention also encompasses the following aspects of the invention.

A method of determining contact lens wear of a patient susceptible to a condition, the method comprising:

a) optionally determining a baseline concentration of interleukin-17A (IL-17A) in a sample of unstimulated tear fluid from the patient previously obtained from the patient;

b) determining the concentration of IL-17A in a stimulated tear sample previously obtained from the patient after stimulating sensory neurons of the patient's cornea; and

c) classifying said patient as susceptible to symptomatic contact lens wear if

i) The concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to a symptom, and/or

ii) the concentration of IL-17A in the stimulated tear sample is greater than the baseline concentration of IL-17A.

A method of determining a contact lens wearer for whom a patient is predisposed to being asymptomatic, the method comprising:

a) determining a baseline concentration of IL-17A in a patient's unstimulated tear sample previously obtained from the patient;

b) determining the concentration of IL-17A in a stimulated tear sample previously obtained from the patient after stimulating sensory neurons of the patient's cornea; and

c) classifying the patient as being prone to asymptomatic contact lens wearers if the concentration of IL-17A in the stimulated tear sample is less than 150% of the baseline concentration of IL-17A.

A method of selecting a treatment for a patient in need of vision correction, the method comprising:

a) optionally determining a baseline concentration of interleukin-17A (IL-17A) in a sample of unstimulated tear fluid from the patient previously obtained from the patient;

b) determining the concentration of IL-17A in a stimulated tear sample previously obtained from the patient after stimulating sensory neurons of the patient's cornea; and;

c) providing a therapeutic prescription to the patient to prevent or reduce discomfort associated with contact lens wear when

i) The concentration of IL-17A in the stimulated tear sample is at or above a predetermined cutoff value associated with contact lens wear that is predisposed to a symptom, and/or

ii) the concentration of IL-17A in the stimulated tear sample is greater than the baseline concentration of IL-17A.

Any of these additional aspects optionally include one or more additional features disclosed with reference to other aspects of the invention, and in particular with reference to other methods of the invention, such as where corneal stimulation and/or collection of tear samples is part of the invention.

The following examples illustrate certain aspects and advantages of the present invention, which should not be construed as limiting.

Example 1:

this project was performed according to the principles of the Declaration of Helsinki, and was approved by the Melbourne Human Research Ethics Committee (Health Sciences Subcommittee, HREC # 1443431). All participants provided written informed consent for participation.

The target is as follows: to further understand the ocular inflammatory response, clinical and immunological techniques are used to determine in persons experiencing contact lens discomfort.

Designing: prospective, cross-sectional clinical studies.

The participants: this study involved 38 adult participants of full-time silicone-hydrogel soft contact lens wearers. Participants were presented with a validated contact lens Dry eye questionnaire (CLDEQ-8)²²Score (n ═ 17 'asymptomatic', CLDEQ-8 score<9; 21 'symptomatic' and CLDEQ-8 score ≧ 13) into subgroups.

The method comprises the following steps: a full anterior eye examination (one contact lens and one no contact lens) was performed at two study visits separated by one week. At visit 1, participants were present without contact lenses and were not wearing at least 24 hours. Written informed consent was obtained, followed by: overall ophthalmic and medical history, assessment of dry eye symptoms (ocular surface disease index, OSDI)³⁸And assessment of symptoms in dry eye, SANDE³⁹Questionnaires) and a range of clinical approaches. The tests included assessment of tear volume osmolarity, ocular redness, tear stability, ocular surface staining, infrared imaging of meibomian glands, tear production, and basal tear collection. Basal tear samples (approximately 5. mu.l/eye) were collected from the inferior temporal culo-caecum (cul de sac) of the participant's eyes using a glass microcapillary (Drummond Scientific 20. mu.l MicroCap) as previously described¹Samples with flow rates of 1 to 3 μ l/min were used only (i.e., excluding any 3 μ l sample collected in less than 60 seconds.) after collection, the samples were centrifuged and stored at-80 ℃ until needed for cytokine analysis. the concentration of the interleukins was determined from basal tears using multiple cytological bead arrays this method involves multiple Cytological Bead Arrays (CBA) for quantitative analysis of IL-2, IL-4, IL-6, IL-10, IL-17A, TNF- α, and IFN- γ (human Th1/Th2/Th17 kit, San rosy BD biosciences, USA), a flow cytometer II (Becton Dickinson biochem, USA), a change in the percentage of detectable interleukins in Becton Dickinson facsto (Becton array, inc., BD), new jersey) was used and the percentage of change in the content of the samples was measured in Becton array (Becton software) relative to baseline.

On visit 2, participants worn their usual contact lenses. To minimize any potential effect of daily variation, visit time for visit 2 was approximately the same time of day (± 1 hour) at visit 1. The 2 nd visit of the participants was asked to ensure that the contact lenses were worn for several hours (average period: 6.6 hours). Similar evaluations were made at both visits. In addition, visit 2 participants answered questionnaires to quantify the severity of lens discomfort (validated contact lens dry eye questionnaire-8, CLDEQ-8 and conventional designed 'bring home questionnaire' (THQ), including 100mm visual simulation scoring to measure simultaneous 'contact lens comfort' and 'contact lens dryness'). Contact lens comfort measurements were recorded using THQ at two time points: (i) when the glasses are about to be worn in the morning (AM), and (ii) at the visit of the afternoon (PM) study.

Statistical analysis: since the common attribute between eyes is thought to be an inflammatory response, data from the right and left eyes of individual participants were averaged to give a single value for each parameter. Data were analyzed using the GraphPad Prism 5 Software package (GraphPad Software, San Diego, USA). Descriptive statistics are summarized as mean ± SEM of parameter data. Data normality was assessed using the agostio (D' Agostino) and Pearson (Pearson) bus tests. Comparisons between groups were performed as needed using the Steady's t assay, the analysis of variance (ANOVA), or the Mann-Whitney U assay. Chi-square verification is used to compare discrete variables. Using Spearman (r)_s) Correlation coefficient studies pairwise correlation statistical significance an α value of 0.05 was used.

As a result: at baseline, there was no significant difference in major clinical signs (p >0.05) between asymptomatic and symptomatic contact lens wearers and no signs indicative of dry eye. Persons experiencing contact lens discomfort have a higher content of IL-17A (122.6 ± 23.7 versus 44.0 ± 10.0pg/mL, p ═ 0.02) and reduced tear stability after several hours of lens wear (6.3 ± 1.1 versus 10.4 ± 1.6 seconds, p ═ 0.03). Tear IL-17A content correlates with I-SOD (r 0.43, p 0.01) and CLDEQ-8 score (r 0.40, p 0.01).

And (4) conclusion: contact lens wear discomfort occurs in people with normal tear film volume osmolarity and no clinical signs of dry eye disease, and is associated with higher levels of the proinflammatory interleukin IL-17A in the tear film. The results of this study provide evidence of a correlation between the malaise response and low grade ocular surface inflammation.

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