Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-06-26
2004-06-15
Saunders, David (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
Reexamination Certificate
active
06750029
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to diagnostic and therapeutic methods based upon the development of cellular immunity to immune privileged antigens and its role in the etiology of paraneoplastic neuronal disorders and tumor immunity, among other conditions.
BACKGROUND OF THE INVENTION
Constant surveillance of epitopes throughout those structures in the body accessible to the immune system provides a very effective means for recognizing and maintaining “self” and destroying epitopes and their carriers which invade the body or arise pathologically, such as infectious microorganisms. One important role of immune surveillance is the recognition and destruction of neoplastic cells that are believed to arise continuously in the body and for the most part are eliminated by the immune system before becoming detectable. However, examples of naturally-occurring tumor immunity have been elusive. Cytotoxic T lymphocytes, key participants in effective immune surveillance, are not expanded in patients with active tumors, even when these tumors express what are believed to be tumor-specific antigens such as the MAGE/MART antigens of melanoma.
Effective tumor immunity has been documented, however, in individuals with paraneoplastic neuronal disorders (PNDs). These syndromes are poorly understood diseases in which serious effects of cancer in the body occur in the nervous system without any direct involvement of the tumor. PND patients typically present to physicians with neurologic dysfunction unaware that they harbor a tumor. For example, patients with ovarian or breast cancer who develop paraneoplastic cerebellar degeneration (PCD) have an effective tumor immune response (3,4,5; reviewed in 1,2,6), and moreover, the tumor expresses neuron-specific proteins (antigens). These patients have in circulation and in the cerebrospinal fluid (CSF) antibodies against these tumor cell antigens, which also cross-react with the same proteins expressed in neurons, termed onconeural antigens. A high titer antibody recognizes the intracellular antigen cdr2 expressed in the ovarian or breast tumor present in PCD patients (10); and also recognizes the antigen in Purkinje neurons of the cerebellum (10). However, as will be elaborated below, the existence of this antibody does not account for the etiology of the PND nor for effective tumor killing.
Certain regions of the body, such as the brain, eye, and testis, are protected from immune surveillance, these sites are referred to as immune privileged. Based on the above observations, the immune system is proposed to initiate PCD by recognizing the normally immune-privileged antigen cdr2 (10) when it is ectopically expressed in gynecologic tumors. This immune response is associated clinically with effective tumor immunity, and is believed to lead to the recognition and destruction of Purkinje neurons expressing cdr2. cDNAs encoding several of the target antigens have been cloned, for example, cdr2 which has been shown to be the correct tumor antigen (9,54). However, because the target neuronal antigen is cytoplasmic, the role of circulating and cerebrospinal fluid (CSF) antibodies against these antigens in the pathogenesis of PCD is questionable. Moreover, attempts to reproduce the disorder by passive or active transfer of antibodies have failed (11,12,13). As the target organ, the brain, is immune privileged, and furthermore the target antigen is cytoplasmic, the etiology of the paraneoplastic syndrome is difficult to reconcile. This is further confounded by the apparent absence of a cellular immune response against tumor antigens in general and the apparent absence of a cellular immune response in PCD. No cytotoxic T lymphocytes were found against the cdr2 protein using autologous dendritic cells in a patient with PCD (47). The etiology of tumor immunity in PND is enigmatic.
As described above, the paraneoplastic syndromes are serious conditions associated with tumors and frequently affect the central nervous system; these disorders are collectively referred to as paraneoplastic neuronal disorders (PND). For example, one common paraneoplastic disorder which is seen in patients with breast or ovarian cancer is paraneoplastic cerebellar degeneration, or PCD, in which a progressive and severe neurological dysfunction occurs involving the cerebellum, leading to dyscoordination of the legs and arms, dizziness and double vision. Frequently, these symptoms appear before the diagnosis of cancer. In another example of neurological degeneration, Hu syndrome is associated with small cell lung cancer and antibodies to the onconeural antigen Hu. In other examples, opsoclonus, or spontaneous, chaotic eye movements, and myoclonus, jerky body movements, may accompany breast cancer, fallopian tube cancer, or small cell lung cancer, and are associated with antibodies to the onconeural antigen Nova.
The target onconeural antigens have yet to be identified for some disorders believed to be paraneoplastic. Patients with Hodgkin's disease and other lymphomas may develop subacute cerebellar degeneration that is believed to be immune mediated (22,42). Eaton-Lambert syndrome, a condition causing weakness in the limbs, may also accompany intrathoracic tumors such as lung cancer and is believed to be immune mediated (2). Some patients who develop spinal cord dysfunction (e.g., myelopathy), motor neuron diseases, blindness and other neurologic symptoms are found to have specific sets of underlying tumors and are believed to have immunity to unknown or partially-characterized onconeural antigens (2,37). Less well understood, the incidence of the muscle diseases dermatomyositis and polymyositis is increased in cancer patients. The dermatologic condition vitiligo, in which melanocytes producing skin pigment are destroyed, appears associated with a decrease in incidence of melanoma. It is thus apparent that an association exists between tumors, and in some cases tumor immunity, and the sites of the paraneoplastic disorder symptoms, perhaps through the existence of some common antigens.
Several lines of evidence suggest the existence of naturally-occurring tumor immunity in PND patients. PND-associated tumors are typically occult (24,25); in several cases they have been identified only by microscopic analysis of suspect organs following exploratory surgery or at autopsy. Patients with PND-associated tumors have significantly-limited disease and an improved tumor prognosis relative to patients with histologically-identical tumors unassociated with PND (20,24,26-28). In some cases PND-associated tumors have been documented to regress with the onset of autoimmune neurologic disease (7).
Specific clinical data regarding anti-tumor immunity is available for several of the PNDs. Patients with paraneoplastic encephalomyelitis harbor high titers of an antibody termed Hu and small cell lung cancers (SCLCa); their tumors are typically limited to single nodules (53/55 [96%] patients in the most complete study published [3]). This is a remarkable finding given that most SCLCa patients from unselected series (over 60%) have widely metastatic disease at the time of diagnosis (and no detectable titers of Hu antibody). In addition, fifteen percent of SCLCa patients without PND nonetheless have detectable titers of the Hu antibody (20). These patients have statistically significant increases in the frequency of limited stage disease, complete response to chemotherapy and longer survival (3,5). These results suggest that anti-PND antibodies may be associated with suppression of tumor growth independently from their association with neurologic disease.
There are also firm associations between the presence of the Nova (Ri) (28) and Yo (10) antibodies in PND patients and clinically-limited malignancy. Both antibodies are found in women with gynecologic cancer. Of 52 Yo-antibody-positive patients with breast or ovarian cancer (4), two-thirds (34/52) presented with neurologic symptoms prior to the diagnosis of cancer, and 87% (45/52) had limited oncologic disease when diagnos
Albert Matthew L.
Bhardwai Nina
Darnell Robert B.
Klauber & Jackson
Saunders David
The Rockefeller University
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