FIELD OF THE DISCLOSURE
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The disclosure relates to the detection of a soluble form of CD200 found in biological fluids including bodily fluids as well as assays useful for diagnosing and monitoring medical conditions associated with elevated levels of CD200, such as cancer.
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TO THE DISCLOSURE
CD200 is a transmembrane surface protein broadly expressed on a variety of cell types and delivers immunoregulatory signals through binding to receptor (CD200R) expressed on monocytes/myeloid cells and T lymphocytes. Stimulation of CD200R triggers an immune suppression response that is of interest medically in the treatment of autoimmune disorders including rheumatoid arthritis, lupus, asthma and in graft rejection and fetal loss.
Inhibition of the CD200:CD200R cascade inhibits CD200-mediated immune suppression, and thus augments the immune response. Agents that disrupt this interaction accordingly are of interest for the treatment of infectious diseases and cancers, and particularly hematopoietic cancers including leukemia, multiple myeloma and lymphoma as well as melanoma and other cancers (Moreaux et al. Biochem. Biophys. Res. Commun., 2008, 366:117-22). It has been suggested that certain AML tumour cells display an upregulated level of membrane-bound CD200, which can be diagnostic for tumours of this type. Various groups have also reported cellular CD200 overexpression associated with CLL, multiple myeloma, and melanoma (Petermann et al, J. Clin. Invest., 2007, 117(12):3922).
As a membrane-bound protein, cellular CD200 can be detected using cell or tissue-based assays, such as flow cytometry or immunohistochemical staining methods. The use of these techniques to detect cell surface CD200 overexpression in subjects presenting with CLL has been suggested, for instance, in US2005/0129690 to Bowdish et al published Jun. 16, 2005. However, it would be desirable to provide methods that are simple in their format, to facilitate detection of CD200, particularly in subjects afflicted with tumours and other medical conditions in which CD200 is overexpressed relative to healthy subjects.
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OF THE DISCLOSURE
It has now been found that a soluble form of CD200 is detectable in biological fluids including serum. Moreover, the level of CD200 detectable in the serum of subjects presenting with CD200-overexpressing cancers, exceeds the level of CD200 detectable in the serum of control subjects. The present disclosure therefore provides an assay useful to detect soluble CD200 in a sample extracted from a subject, wherein the assay is performed on a sample of biological fluid extracted from the subject. The disclosure further provides a method for identifying a subject having, or at risk for, a medical condition associated with increased CD200 levels and/or associated with cells and/or tumours that over-express CD200, comprising the steps of determining the level of soluble CD200 in the subject, comparing that soluble CD200 level to the soluble CD200 level in a control subject, wherein an elevated soluble CD200 level is diagnostic for a CD200 associated medical condition. The disclosure further provides for the use of the assay to monitor a subject for progression or regression of such a medical condition, such as during and after medical treatment. Also provided by the present disclosure is a method of medical treatment in which a subject is first diagnosed using the assay of the present disclosure, and is then treated, for example, treated to inhibit the CD200:CD200R signalling cascade.
Thus, in one of its aspects, the present disclosure provides a method for determining a level of soluble CD200, the method comprising contacting a biological fluid from a subject with an agent that specifically binds soluble CD200 and detecting the binding thereof to determine the level of soluble CD200.
In another aspect, the disclosure provides a method for identifying a subject having an elevated CD200 level, the method comprising the step of assaying a biological fluid from the subject to determine a level of soluble CD200, wherein a level above control indicates the subject has elevated soluble CD200 levels.
In another aspect, the disclosure provides a method for identifying a subject having cells that overexpress cellular CD200, the method comprising the step of assaying biological fluid from the subject to determine the level of soluble CD200, wherein a level above control indicates the presence of said cells.
In a related aspect, the present disclosure provides a method for identifying a subject having or at risk for a medical condition associated with elevated CD200, the method comprising the steps of:
a) obtaining a sample of biological fluid from said subject; and
b) determining a level of soluble CD200 in said sample,
wherein a soluble CD200 level above control indicates said medical condition.
In another aspect, the present disclosure provides a method for monitoring progression in a subject of a medical condition associated with elevated CD200, the method comprising the steps of:
a) at a first time point, determining a level of soluble CD200 in a first sample of biological fluid from the subject; and
b) comparing the level of soluble CD200 in a subsequent sample of biological fluid taken from said subject at a second time point different from the first time point;
wherein a difference in the soluble CD200 levels at the first time point compared to the second time point indicates modulated progression of the condition.
In a further aspect, the present disclosure provides a method of medical treatment useful to control progression of a medical condition associated with overexpression of cellular CD200, comprising the steps of:
a) identifying a subject having cells that overexpress cellular CD200 as determined by the assay method of the present disclosure, and
b) treating the subject with an agent that inhibits signalling via the CD200:CD200R pathway.