WO2022221423A1 - Treatment of autoimmune anti-nmda-receptor encephalitis - Google Patents

Abstract

Disclosed herein are methods of treating autoimmune anti-NMDAR encephalitis with L-4- chlorokynurenine, L-4-chlorokynurenine in combination with probenecid, and 7-chlorokynurenic acid, and compositions thereof.

Description

TREATMENT OF AUTOIMMUNE ANTI-NMDA-RECEPTOR ENCEPHALITIS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/174,215 filed on April 13, 2021, the disclosure of which are incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention relates to the use of L-4-chlorokynurenine (L-4-CI-KYN) and 7-chlorokynurenic acid (7-CI-KYNA), and compositions thereof, for the treatment of autoimmune anti-NMDA receptor encephalitis.

BACKGROUND

[0003] The /V-methyl-D-aspartate receptor (NMDAR) is a complex transmembrane receptor comprised of two GluNl and two GluN2 subunits (also known as NR1 and NR2). Autoimmune anti-NMDAR encephalitis is an inflammatory disorder of the brain. Autoimmune anti-NMDAR encephalitis arises when antibodies against NMDARs engage their targets in the central nervous system (CNS), thereby creating swelling and inflammation and negatively affecting the normal functions of the NMDAR. It is hypothesized that the pathophysiology of NMDAR encephalitis is mediated in part by a decreased level of NMDAR expression on the post-synaptic neuronal surface.

[0004] The clinical presentation of autoimmune anti-NMDAR encephalitis varies. Subjects exhibiting this disorder generally express a viral prodrome, followed by the development of acute psychiatric symptoms, memory problems, seizures, decreased or confused consciousness, and dyskinesias (Kayser 2013). Neurologic symptoms (for example, dyskinesias and seizures) tend to be the initial clinical manifestation for younger patients (<18 years) T. Armanue, et al., The Journal of Pediatrics, vol. 162, no. 4, pp. 850-856, (2013). Older patients (>45 years) tend to present with memory loss, making differentiation from other dementia-associated disorders difficult (Titulaer 2013). However, a significant clinical tool for diagnosis in women continues to be the presence of tumors: approximately 45% of patients older than 18 years and 9% of girls younger than 14 years present with ovarian teratomas (Titulaer 2013). Autoimmune anti-NMDAR encephalitis can therefore be broadly divided into two categories: classic tumor-associated paraneoplastic disorders (PNDs) and tumor-absent disorders associated with antibodies to neuronal cell-surface or synaptic receptors (Lancaster 2012). The PNDs, with respect to all encephalitis cases, are relatively rare and in most cases affect older women (Bernal 2002).

[0005] Hyperactivation of NMDAR has been associated with memory loss and is implicated in the pathogenesis of various neurodegenerative conditions, including Alzheimer's disease (Lancelot 1998). Hypoactivation on the other hand may be associated with a number of psychiatric symptoms and signs, including psychosis, mania, depression, and may be implicated in a number of psychiatric disorders, including schizophrenia and bipolar disorder (Gunduz-Bruce 2009; Coye 2003; Leon Caballero 2015). Overactive glutamatergic transmission via NMDAR is known to play a key role in several neurologic conditions, such as neuropathic pain for example. However, direct acting (for example, by channel blocking) NMDAR antagonists produce a number of side effects, such as psychosis, which have limited their therapeutic utility. Antagonism of NMDARs can also be achieved through blockade of a modulatory site on the NMDAR, known as the glycine B (GlyB) co-agonist site (Parsons 1997). When compared with classic NMDAR antagonists, GlyB antagonists have a better safety profile and generally do not cause the adverse side effects that are associated with "classic" NMDAR antagonists, including ketamine (Carter 1992; Leeson 1994; Rundfeldt 1994; Zanos 2015).

[0006] One of the most potent and specific GlyB antagonists currently known is 7-CI-KYNA, which is a synthetic, chlorinated analogue of an endogenous neuromodulator, kynurenic acid. 7-CI-KYNA has been shown to prevent excitotoxic and ischemic neuronal damage and has been shown to be anti-depressive in animals if injected intrathecally but does not cross the blood-brain barrier. Thus, its clinical use is limited because it cannot be administered in an oral formulation (Kemp 1988; Rao 1993).

[0007] In contrast, L-4-CI-KYN, a prodrug of 7-CI-KYNA, readily gains access to the central nervous system (CNS) after oral or parenteral administration (Hokari 1996; Lee 2001; Wu 2002; Wu 2000). L-4-CI- KYN is efficiently converted to 7-CI-KYNA within activated astrocytes in the brain and brain levels of 7-CI- KYNA are increased at sites of neuronal injury or excitotoxic insult as a result of astrocyte activation (Lee et al. 2001).

[0008] Methods for the synthesis of a class of 4,6-disubstituted kynurenine derivatives and monosubstituted derivatives, including L-4-CI-KYN, and their use as antagonists to the NMDAR were described in U.S. Patent Nos. 5,547,991 and 9,834,801. Pharmaceutical compositions containing these compounds, and their therapeutic use also were described. Also, L-4-CI-KYN presently is being evaluated as a potential treatment of depression in Phase II clinical studies. However, the use of L-4-CI- KYN in the context of autoimmune anti-NMDAR encephalitis has not been described. [0009] 7-CI-KYNA, which also down-regulates NMDAR activity, disrupts at least the binding of some anti-NMDAR antibodies to NMDAR. Without subscribing to any particular theory, 7-CI-KYNA functions to disrupt this binding, either by 1) blocking binding sites for one or more of anti-NMDAR specific antibodies; and/or 2) inducing conformational changes to NMDAR resulting in alterations to one or more anti-NMDAR antibody binding sites. Such an induced conformational change in the NMDAR is exemplified by Kemp et al. who discloses that 7-CI-KYNA binding to the glycine binding site modifies the conformation of NMDAR such that it does not respond to the binding of glutamate, and thereby has a negative modulatory effect on NMDAR (Kemp 1998). Warikoo et al. discloses that positive allosteric modulators rescue NMDAR function when exposed to NMDAR encephalitis CSF (Warikoo 2018).

[0010] A proposed mechanism of neuronal dysfunction in anti-NMDAR encephalitis involves anti- NMDAR antibodies binding to the receptors leading to receptor cross-linking and internalization. The loss of NMDARs from the neuron surface eliminates NMDAR-mediated synaptic function resulting in the symptoms observed in patients with anti-NMDAR encephalitis.

[0011] The clinical presentation of autoimmune NMDAR encephalitis varies; however, patients generally express a viral prodrome, followed by the development of acute psychiatric symptoms, memory problems, seizures, decreased or confused consciousness, and dyskinesias (Kayser 2013). Neurologic symptoms (e.g., dyskinesias and seizures) tend to be the initial clinical manifestation for younger patients (<18 years) (Armangue). Older patients (>45 years) tend to present with memory loss, making differentiation from other dementia-associated disorders difficult (Titulaer 2013).

[0012] Anti-NMDAR encephalitis affects predominantly children and young adults (median age, 21 years), with a predominance of cases in females (4:1) that becomes less evident after the age of 45 years (Titulaer 2013). Up to 58% of affected young female patients have an ovarian teratoma (extragonadal teratomas are a rare cause); in men and children, the association with tumors is less frequent (Titulaer 2013). Young children typically present with insomnia, seizures, abnormal movements, or a change in behavior such as irritability, temper tantrums, agitation, and reduction of verbal output (Dalmau 2018). Teenagers and adults more often present with psychiatric symptoms, including agitation, hallucinations, delusions, and catatonia, which may lead to hospital admission for psychosis (Dalmau 2018). The disease progresses in a period of days or weeks to include reduction of speech, memory deficit, orofacial and limb dyskinesias, seizures, decreased level of consciousness, and autonomic instability manifested as excess salivation, hyperthermia, fluctuations of blood pressure, tachycardia, or central hypoventilation (de Montmollin 2017). Bradycardia and cardiac pauses are infrequent but require a temporary pacemaker in some patients (Dalmau 2018). [0013] One month after disease onset, regardless of the symptoms at presentation, most children and adults have a syndrome that combines several of the above-mentioned symptoms; in approximately 5% of patients, the disease may remain monosymptomatic (e.g., psychiatric symptoms) (Titulaer 2013). MRI of the head is abnormal in 30% of affected patients, mainly showing increased fluid-attenuated inversion recovery (FLAIR) signal involving the cortical, subcortical, or cerebellar regions (Titulaer 2013). The diagnosis of anti-NMDAR encephalitis currently is confirmed by the detection of CSF antibodies against the GluNl subunit of the NMDAR; serum testing is less reliable, with false negative results in up to 14% of cases (Gresa-Arribas 2014).

SUMMARY OF THE INVENTION

[0014] The invention and its various embodiments are set out in the claims that form part of this patent application.

[0015] The invention generally relates to methods of treatment of autoimmune anti-NMDAR encephalitis. A method of treatment of autoimmune anti-NMDAR encephalitis according to the invention includes a step of administering to the subject in need thereof a therapeutically effective amount of L-4-CI-KYN.

[0016] In some methods of treatment according to the invention, the L-4-CI-KYN is administered as a daily dose ranging from about 50 mg/day to about 3,000 mg/day, preferably about 360 mg/day, 720 mg/day, 1,080 mg/day, 1,440 mg/day, 1,800 mg/day, 2,160 mg/day, 2,520 mg/day or 2,880 mg/day. In some methods of treatment according to the invention, the L-4-CI-KYN is administered as a unit dose, optionally with a pharmaceutically acceptable carrier or excipient, where the amount of L-4-CI-KYN in the unit dose ranges from about 50 mg to about 1,800 mg, preferably 360 mg, 720 mg, 1,080 mg or 1,440 mg.

[0017] In some methods according to the invention, the L-4-CI-KYN is administered together with an effective amount of an additional anti-encephalitic treatment, such as an anti-inflammatory agent. Appropriate anti-inflammatory agents include, for example, steroids and NSAIDS.

[0018] Another embodiment of the invention is a method of treating autoimmune anti-NMDAR encephalitis including a step of administering to the subject in need thereof a therapeutically effective amount of 7-CI-KYNA that is administered to the brain via the cerebral spinal fluid (CSF) or otherwise by techniques known to persons skilled in the art such as intrathecal infusion.

[0019] Another embodiment of the invention is a method of treating autoimmune anti-NMDAR encephalitis, which includes a step of administering to the subject in need thereof a therapeutically effective amount of L-4-CI-KYN in combination with probenecid. In some methods of treatment according to the invention, the effective amount of the L-4-CI-KYN is administered daily in a dose ranging from about 50 mg/day to about 3,000 mg/day, preferably about 360 mg/day, 720 mg/day, 1,080 mg/day, 1,440 mg/day, 1,800 mg/day, 2,160 mg/day, 2,520 mg/day or 2,880 mg/day in combination with probenecid administered daily in a dose ranging from about 250 mg/day to about 2 g/day of probenecid.

[0020] In some methods of treatment according to the invention, the L-4-CI-KYN is administered as a unit dose in combination with probenecid, optionally with a pharmaceutically acceptable carrier or excipient, where the amount of L-4-CI-KYN in the unit dose ranges from about 50 mg to about 1,800 mg, preferably 360 mg, 720 mg, 1,080 mg or 1,440 mg and the amount of probenecid in the unit dose ranges from about 250 mg to about 2 g.

[0021] In some methods according to the invention, the L-4-CI-KYN in combination with probenecid is administered together with an effective amount of an additional anti-encephalitic treatment, such as an anti-inflammatory agent. Appropriate anti-inflammatory agents include, for example, steroids and NSAIDS.

[0022] Yet another aspect of the invention relates to a method of determining the likely responsiveness of a subject suffering from autoimmune anti-NMDAR encephalitis together with treatment by administering L-4-CI-KYN, L-4-CI-KYN in combination with probenecid, or 7-CI-KYNA to the subject, where the method includes obtaining a sample from the subject and assaying the sample to detect antibodies against the NMDAR, and where the presence of such antibodies is indicative of the subject's likely responsiveness to the treatment.

BRIEF DESCRIPTION OF THE FIGURES

[0023] FIG. 1 depicts the apparent mechanism of L-4-CI-KYN, specifically binding of 7-CI-KYNA (the metabolite of L-4-CI-KYN) to the GlyB site of NMDAR which inhibits binding of at least some of the anti- NMDAR specific antibodies by blocking a binding site for anti-NMDAR antibodies and/or inducing allosteric changes in the conformation of NMDAR thereby sufficiently altering anti-NMDAR antibody binding.

[0024] FIG. 2 shows effect of probenecid and L-4-CI-KYN on levels of 4-chlorokynurenine in PFC dialysate. AV-101 = L-4-CI-KYN.

[0025] FIG. 3 shows effect of probenecid and L-4-CI-KYN on levels of 7-chlorokynurenic acid in PFC dialysate. AV-101 = L-4-CI-KYN. DETAILED DESCRIPTION

[0026] The present invention generally relates to methods of treatment of autoimmune anti-NMDAR encephalitis. Without being held to a particular theory for a mechanism of action, it is contemplated that binding by 7-CI-KYNA (the metabolite of 4-CI-KYN) to the GlyB site of the NMDAR in turn inhibits binding of least some of the anti-NMDAR specific antibodies by one or both of these mechanisms: 1) blocking a binding site for anti-NMDAR antibodies; and 2) inducing allosteric changes in the conformation of the NMDAR that in turn alters an anti-NMDAR antibody binding site sufficient to inhibit binding of anti-NMDAR antibodies. Reduction of the binding of anti-NMDAR antibodies would reduce the number of NMDAR that are removed from the neuronal cell surface, and could restore more normal NMDAR function.

[0027] A method of treatment of autoimmune anti-NMDAR encephalitis according to the invention includes a step of administering to the subject in need thereof a therapeutically effective amount of L-4- CI-KYN. "Therapeutically effective" means that the amount of L-4-CI-KYN administered and converted to 7-CI-KYNA acts to disrupt the binding of anti-NMDAR antibodies to NMDAR that is sufficient to produce a clinical improvement in autoimmune anti-NMDAR encephalitis. In some methods of the invention, a therapeutically effective amount of 7-CI-KYNA is administered. A "therapeutically effective" amount of 7-CI-KYNA, is an amount sufficient to reduce or disrupt the binding of anti-NMDAR antibodies to NMDAR that is effective to produce a clinical improvement in autoimmune anti-NMDAR encephalitis.

[0028] The treatment methods of the present invention are expected to produce significant improvement in one or more of the typical clinical presentations in autoimmune anti-NMDAR encephalitis such as improvement in acute psychiatric symptoms, improved memory function, reductions in seizures or dyskinesias, and improvement in consciousness and awareness. Various measures and tools for assessing psychiatric states are well-known to a clinician trained in the field. For example, clinical improvement after drug therapy may be determined by the treating physician, and the clinical global impression (CGI) generally may be used as a summary measure for severity (CGI-S) and improvement (CGI-I) (Guy 1976). As another example, clinical improvement in terms of functional recovery may be evaluated using the modified Rankin Scale (mRS), with improvement in mRS scores obtained after drug therapy (Shin 2018; Kong 2006). Clinical improvement with respect to cognitive assessment may be conducted by monitoring, for example, Montreal Cognitive Assessment scores (MOCA), with increases in MOCA scores obtained with drug therapy (Keddie 2018). Clinical improvement for patients with seizures may be demonstrated by a decrease in the number of seizures after drug therapy (Kong 2018). For dyskinesia symptoms, clinical improvement upon drug therapy may be evaluated using e.g., Abnormal Involuntary Movement Scale (AIMS), the Unified Parkinson's Disease Rating Scale (UPDRS) part IV, the Obeso Dyskinesia Rating Scale, the Rush Dyskinesia Rating Scale, the Clinical Dyskinesia Rating Scale (CDRS), the Lang-Fahn Activities of Daily Living Dyskinesia Scale, the Parkinson Disease Dyskinesia Scale (PDYS-26), and the Unified Dyskinesia Rating Scale (UDysRS). Clinical improvements for memory loss upon drug therapy may be evaluated using tests such as Mini-cognition tests and Mini Mental State Exam (MMSE).

[0029] In a personalized medicine context, the detection of anti-NMDAR specific antibodies as described, for example, in Example 2, provide a prognostic method of determining the likely responsiveness of a subject suffering from autoimmune anti-NMDAR encephalitis to treatment with L-4- CI-KYN or 7-CI-KYNA. This includes obtaining and then testing a sample from the subject and assaying the sample to detect antibodies against the NMDAR, whose interaction with NMDAR is reduced or inhibited by 7-CI-KYNA. The presence of such antibodies is indicative of the subject's likely responsiveness to the treatment.

[0030] L-4-CI-KYN has been synthesized by the methods of U.S. Patent No. 5,547,991. More recent synthesis processes also have been reported in the medical literature, such as Salituro et al. 1994. Additional synthesis methods are described in U.S. Patent No. 9,834,801, published international patent application WO/2014/152835, and International Patent Application No. PCT/US2019/017448. L-4-CI- KYN also is available commercially from various sources, including BOC Sciences (Shirley, NY, USA), Advanced Technology & Industrial Co., Ltd. (Hong Kong, China), and Cambridge Major Laboratories (Germantown, Wl, USA).

[0031] In one aspect, the invention relates to a method of treating autoimmune NMDAR encephalitis, comprising a step of administering to a human subject in need thereof L-4-CI-KYN in combination with probenecid in amounts therapeutically effective to treat autoimmune NMDAR encephalitis.

[0032] Probenecid inhibits both the organic anion transporters (OAT) in the basolateral membrane of cells in the proximal tubule. This results in reduced clearance and increased plasma levels of drugs normally secreted by this mechanism (e.g. penicillin). Probenecid increased brain levels of L-4-CI-KYN by approximately 7-fold in the brain. See FIG. 2. Probenecid increased brain levels of 7-CI-KYNA by approximately 35-fold in the brain. See FIG. 3. Furthermore, probenecid extended the time to Cmax. Consequently, for the treatment methods according to the present invention, the addition of probenecid advantageously allows for a significant reduction in the amount of prodrug administered to achieve the same concentration of the chlorokynurenic acid in the brain. 7-CI-KYNA levels in the brain are also lowered by MRP4, the multidrug resistance-associated protein 4. Therefore, it is believed that probenecid effects are mediated by blocking the OAT and MRP4 transporters, by inhibiting their transport of compounds, and drugs, out of the brain, and out of the blood ultimately for excretion by the kidney.

[0033] In the methods of treatment according to the invention, L-4-CI-KYN is administered as a pharmaceutical formulation. Preferably, pharmaceutical compositions of L-4-CI-KYN comprise a unit dose of L-4-CI-KYN that is formulated for oral administration, together with pharmaceutically acceptable carriers and excipients. In other preferred methods, the L-4-CI-KYN that is formulated as a suppository, together with pharmaceutically acceptable carriers and excipients. In other embodiments, the L-4-CI- KYN is administered in combination with probenecid. In still other embodiments, 7-CI-KYNA is administered as a pharmaceutical formulation, preferably, together with pharmaceutically acceptable carriers and excipients. Preferably, such formulations of 7-CI-KYNA are be administered as an intrathecal infusion or intracerebral injection.

[0034] "Pharmaceutical unit dose," "unit dose," or "unit dose form" means a single dose of L-4-CI-KYN, probenecid, or 7-CI-KYNA, which is administered to a subject. In some embodiments, the unit dose can be readily handled and packaged, remaining as a physically and chemically stable unit dose. For example, in a particular embodiment, an oral unit dose may be a single tablet, while in another embodiment, an oral unit dose may be more than one tablet. In some embodiments, the unit dose form comprises both L-4-CI-KYN and probenecid. In other embodiments, the unit doses of the prodrug and probenecid are separate. In general, it is preferred to administer the prodrug and probenecid in a combined unit dose or in separate doses administered simultaneously, or within an hour of each other.

It may also be preferred to administer the combined unit dose or separate doses once daily, twice daily, thrice daily or more so as to provide the subject with a preferred dosage level per day.

[0035] In some methods of treatment according to the invention, the L-4-CI-KYN, formulated for oral administration, is administered as a unit dose, optionally with a pharmaceutically acceptable carrier or excipient, where the amount of L-4-CI-KYN in the unit dose ranges from about 50 mg to about 1,800 mg. For example, the amount of L-4-CI-KYN in the unit dose is preferably from about 260 mg to about 1,540 mg, more preferably either about 260 mg to about 460 mg, about 310 mg to about 410 mg, about 460 mg to about 980 mg, about 980 mg to about 1,180 mg, about 1,030 mg to about 1,130 mg, about 1,340 to about 1,540 mg, about 1,390 mg to about 1,490 mg and most preferably about 360, 720, 1,080, or 1,440 mg. In some methods of the invention the unit dose is administered one or more times per day.

In some embodiments, the daily dose does not exceed 2,900 mg/day. [0036] In some methods of treatment according to the invention, the L-4-CI-KYN is administered in combination with probenecid. These compositions may be administered as a co-formulated composition or as separate compositions that are administered contemporaneously or sequentially but administered in a manner that achieves the therapeutic benefit of co-administration. Preferably, pharmaceutical compositions of probenecid comprise a unit dose of the probenecid that is formulated for oral administration, together with pharmaceutically acceptable carriers and excipients.

[0037] In some methods of treatment according to the invention where L-4-CI-KYN is administered in combination with probenecid, the probenecid is administered as a unit dose, optionally with a pharmaceutically acceptable carrier or excipient, where the amount of probenecid in the unit dose ranges from about 250 mg to about 2,000 mg. For example, the amount of probenecid in the unit dose is preferably from about 300 mg to about 1,800 mg, more preferably either about 400 mg to about 1,600 mg, about 500 mg to about 1,400 mg, and from about 600 mg to about 1,200 mg, from about 700 mg to about 1,200 mg, and about 800 mg to about 1,000 mg.

[0038] It is contemplated that the exact dosages of both L-4-CI-KYN and probenecid to be administered within the ranges described for the present invention are to be safe and effective as would be consistent with regulatory agency approvals. It is also contemplated that the unit dose form or forms may be administered one or more times per day, in order to extend the time period in which L-4-CI-KYN levels or its metabolites are elevated to a result in a therapeutically effective amount of chlorokynurenic acid.

[0039] It is contemplated that the duration of the dosing regimens for the compositions of the present invention are therapeutically effective. While a daily dosing regimen is contemplated, this would preferably be from about 5 to about 30 days, including shorter and longer dosing regimens as determined by a subject's physician. In particular, dosing regimens of about 7 to about 24 days, and about 12 to about 16 days are expressly contemplated. A daily dosing regimen may include administration of one or more unit doses per day. In a preferred embodiment, the daily dose of probenecid does not exceed 2 g per day.

[0040] Other pharmaceutical compositions of L-4-CI-KYN comprise a unit dose of L-4-CI-KYN that is formulated as a suppository, together with pharmaceutically acceptable carriers and excipients. L-4-CI- KYN may be administered rectally via a suppository. In some embodiments, the unit dose, where the L- 4-CI-KYN is formulated as a suppository, the amount of L-4-CI-KYN in the unit dose ranges from about 50 mg to about 1,800 mg. For example, the amount of L-4-CI-KYN in the unit dose is preferably from about 260 mg to about 1,540 mg, more preferably either about 260 mg to about 460 mg, about 310 mg to about 410 mg, about 460 mg to about 980 mg, about 980 mg to about 1,180 mg, about 1,030 mg to about 1,130 mg, about 1,340 to about 1,540 mg, about 1,390 mg to about 1,490 mg and most preferably about 360, 720, 1,080, or 1,440 mg. In some methods of the invention the unit dose is administered one or more times per day. In some embodiments, the daily dose does not exceed 2,900 mg/day.

[0041] In another embodiment, 7-CL-KYNA is administered as an intrathecal infusion. Preferably, pharmaceutical compositions of 7-CL-KYNA comprise a unit dose of 7-CL-KYNA that is formulated for intrathecal administration, together with pharmaceutically acceptable carriers and excipients.

Intrathecal formulations are sterile isotonic solutions. An intrathecal formulation requires chemical, physical, and thermal stability under all conditions associated with intrathecal delivery via an external or implantable pump. Further, biological activity must not be decreased through surface adsorption upon incubation. 7-CL-KYNA formulations appropriate for intrathecal delivery must also contain a sufficient amount of biologically acceptable salt to maintain fluid tonicity. Preferably, a 7-CL-KYNA formulation contains sufficient salt to be isotonic, within physiologically acceptable limits, with human blood or cerebral spinal fluid. A preferred salt is sodium chloride (NaCI), but other biologically acceptable salts may be used, such as potassium chloride (KCI) , calcium chloride (CaCI₂), and magnesium chloride (MgCI₂). The salt may be one salt or a combination of salts. Intrathecal formulations for administration, according to some embodiments, comprise 2 to 40 mg 7-CL-KYNA, and comprise, for example, 187 mM NaCI, 2.6 mM KCI, 1.2 mM KH₂P0₄, 26 mM NaHC0₃, 10 mM D-glucose, 1.1 mM CaCI₂, and 0.9 mM MgCI₂. In some methods of the invention, the intrathecal formulation is administered one or more times a day. The daily dose of 7-CL-KYNA ranges from 2 mg/day to 40 mg/day.

[0042] In yet another embodiment, 7-CL-KYNA is administered as an intracerebral injection (Dagdeviren 2018). An intracerebral formulation requires chemical, physical, and thermal stability under all conditions associated with intracerebral delivery via an external or implantable pump. Further, biological activity must not be decreased through surface adsorption upon incubation. 7-CL-KYNA formulations appropriate for intracerebral delivery must also contain a sufficient amount of biologically acceptable salt to maintain fluid tonicity. Preferably, a 7-CL-KYNA formulation contains sufficient salt to be isotonic, within physiologically acceptable limits, with cerebral fluid. A preferred salt is sodium chloride (NaCI), but other biologically acceptable salts may be used, such as potassium chloride (KCI) , calcium chloride (CaCI₂), and magnesium chloride (MgCI₂). The salt may be one salt or a combination of salts. Formulations for administration by intracerebral injection, according to some embodiments, comprise, for example2 to 40 mg 7-CL-KYNA, and comprise, for example, 187 mM NaCI, 2.6 mM KCI, 1.2 mM KH₂P0₄, 26 mM NaHC0₃, 10 mM D-glucose, 1.1 mM CaCI₂, and 0.9 mM MgCI₂. In some methods of the invention, the intracerebral formulation is administered one or more times a day. The daily dose of 7-CL-KYNA ranges from 2 mg/day to 40 mg/day.

[0043] In some methods of treatment according to the invention, administering L-4-CI-KYN produces a blood plasma level of L-4-CI-KYN ranging from about 2 pg/mL to about 55 pg/mL within about 0.5 to about 6 hours after administration. In preferred embodiments of these methods, the L-4-CI-KYN is administered together with a pharmaceutically acceptable carrier or excipient. It is contemplated that the dosages of L-4-CI-KYN to be administered produce plasma levels of 7-CI-KYNA ranging from about 15 ng/mL to about 550 ng/mL. See U.S. Patent No. 9,993,453 at Figure 2. Plasma levels of 7-CI-KYNA ranging from about 15 ng/mL to about 65 ng/m, from about 65 ng/mL to about 300 ng/mL and from about 300 ng/mL to about 550 ng/mL are expressly contemplated.

[0044] In some methods of treatment according to the invention, the L-4-CI-KYN is administered as one or more unit doses per day, with a daily dose ranging from about 50 mg/day to about 3,000 mg/day, preferably 360 mg/day, 720 mg/day, 1,080 mg/day, 1,440 mg/day, 1,800 mg/day, 2,160 mg/day, 2,520 mg/day or 2,880 mg/day. It is also contemplated that the unit dose may be administered one or more times per day, and over multiple days, such a two, three or four times weekly or every other day, in order to extend the time period in which L-4-CI-KYN levels are elevated to a therapeutically effective amount of 7-CI-KYNA.

[0045] In some methods of treatment according to the invention, the 7-CI-KYNA is administered as one or more unit doses per day, with a daily dose ranging from about 0.36 g/day to 1.8 g/day.

[0046] The precise dose may be determined by the health care provider by initiating treatment at an appropriate dose, for example, within the dose ranges described above or as otherwise may be determined, and then monitoring the health and symptoms of the treated patient to permit adjustment of the dose by small increments or as determined. Preferably, the patient will be reevaluated periodically to determine the improvement and clinical benefit of the administration of L-4-CI-KYN or 7- CI-KYNA. Generally, the dose may be administered in a single dose or as multiple doses at intervals as may be appropriate, for example in two, three or four doses per day to achieve a therapeutically effective amount of L-4-CI-KYN or 7-CI-KYNA, respectively.

[0047] It is contemplated that the dosing regimens for the methods of treatment of the invention are therapeutically effective. While a daily dosing regimen is contemplated, as described above, this would preferably be from about 5 to about 30 days, including shorter and longer dosing regimens as determined by a patient's physician. In some embodiments where the dosing regimen is over the period of several days, a physician may start with the highest safe daily dose for oral administration, for example, 2,880 mg/day of L-4-CI-KYN, depending on the patient, and reduce the daily dose based on clinical improvement. For example, neurological outcome is assessed with the modified Rankin scale (mRS) and mini-mental state examination (MMSE), described above. Patients are described as having full recovery if they return to their jobs (mRS 0, MMSE 29-30); mild deficits, if they return to most activities of daily living and remain stable for at least 2 months (mRS 1-2; MMSE >25-28); and severe deficits for all other cases.

[0048] In some methods according to the invention, the L-4-CI-KYN, L-4-CI-KYN in combination with probenecid, or 7-CI-KYNA, is administered together with an additional anti-inflammatory and/or anti- encephalitic treatment. Additional anti-encephalitic treatments include reduction or elimination of antibodies by plasma exchange (e.g., by PLEX to filter antibodies out of the host's blood), or by administering anti-inflammatory drugs such as steroids, glucocorticoids, for example, prednisone, methylprednisolone, and dexamethasone, NSAIDs or cyclosporin, or administration of intravenous immunoglobulins that bind to host antibodies, rituximab, or cyclophosphamide 9 (Dalmau 2018). Common first-line encephalitis treatments include intravenous human immunoglobulins, plasmapheresis, therapeutic plasma exchange, and steroids. Second line treatments include immunotherapy with cyclophosphamide or rituximab or both (Dalmau 2011; Staley 2018).

[0049] In some methods of treatment according to the invention, the subject in need of treatment needs relief from symptoms selected from the group consisting of loss of memory, seizures, decreased or confused consciousness, and dyskinesias. Administration of L-4-CI-KYN, L-4-CI-KYN in combination with probenecid, or 7-CI-KYNA, according to methods of the invention results in relief of these symptoms.

[0050] Pharmaceutical compositions of the invention include various dosage forms of L-4-CI-KYN and probenecid, either alone, or in combination, may be used in methods of the invention, including, for example, tablets, capsules, liquid suspensions, solid solutions, soft gels, injectable formulations, topical formulations, or transdermal formulations, suppositories and formulations for nasal delivery. A person skilled in the art will understand how to prepare and formulate the compositions of the present invention for administration to achieve their intended therapeutic effects. Additionally, a dosage form may also be a modified release form such as, but not limited to, a bi-modal or extended release form. [0051] The pharmaceutical compositions may be prepared by conventional methods known in the art of pharmaceutical formulations. For example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). In a solid dosage form, L-4-CI-KYN or probenecid may be admixed with at least one pharmaceutically acceptable excipient such as, for example, sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as, for example, cellulose derivatives, starch, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, such as, for example, glycerol,

(d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, such as, for example, paraffin, (f) absorption accelerators, such as, for example, quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, such as, for example, kaolin and bentonite, and (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0052] Pharmaceutically acceptable adjuvants known in the pharmaceutical formulation art may also be used in the pharmaceutical compositions. These include, but are not limited to, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms may be ensured by inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. If desired, a pharmaceutical composition may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

[0053] Solid dosage forms as described above may be prepared with coatings and shells, such as enteric coatings and others well known in the art. Some dosage forms may contain pacifying agents, while the same or different dosage forms are formulated to release L-4-CI-KYN and/or probenecid in a certain region of the intestinal tract in a delayed manner.

[0054] Solid dosage forms of the invention may also be formulated as an embedded composition. Non limiting examples of embedded compositions include polymeric substances and waxes in which microencapsulated L-4-CI-KYN and/or probenecid are embedded.

[0055] Suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. [0056] Compositions for rectal administrations are, for example, suppositories that may be prepared by mixing L-4-CI-KYN with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which may be solid at ordinary temperatures but may be liquid at body temperature and, therefore, melt while in a suitable body cavity and release the active component therein.

EXAMPLES

Example 1: Materials and Methods

[0057] Preparation ofAnti-NMDAR antibodies and control: Cerebrospinal fluid (CSF) and serum are obtained from patients with well characterized clinical manifestations of anti-NMDAR encephalitis and high titer anti-NMDAR antibodies. Antibodies to extracellular epitopes of the NR1 subunit of the NMDAR are demonstrated using three different assays as previously reported: immunohistochemistry with rat and human brain, immunostaining of live, non-permeabilized cultures of rat hippocampal neurons, and immunolabeling of HEK293 cells transfected with NR1 or NR1 and NR2 (forming NR1/2 heteromers) (Dalmau 2008). Control serum or CSF samples are obtained from normal individuals and patients undergoing CSF analysis for a variety of disorders not associated with antibodies to the NMDAR; samples are randomly selected from a representative number of cases negative for NR1 antibodies applying similar test and criteria as above.

[0058] Patient or control CSF and serum are collected, filtered, and kept frozen until use. Patient CSF are used at various dilutions in relevant assay buffers without purification, whereas patient immunoglobulins (IG) are purified from 2 ml of serum with Protein L Agarose, dialyzed against PBS pH 7.4, prepared in concentrated in stock solutions (20 mg/ml, PBS, pFI7.4, supplemented with 0.5% FBS), and stored at -80°C. IgG stock solution concentration is adjusted with PBS pH 7.4 containing 0.1% FBS before use. Each IgG preparation is tested for antibody reactivity by staining rat brain sections or H EK cells expressing human NR1/NR2 heteromers of the NMDAR as previously described (Dalmau 2008; Dalmau 2007).

[0059] Cell culture and patient antibody binding: Cell culture and binding are performed as previously described (Flughes 2010). Briefly, isolated rat hippocampi are placed in Ca²⁺-free HBSS (HBSS;

Invitrogen) containing 1% papain for 20 min, triturated in Basal Media Eagle (Invitrogen) supplemented with B-27 (Invitrogen) and plated at 100,000 or 400,000 (for biotinylation) cells per milliliter in Neural Basal (NB) (Invitrogen) supplemented with 10% FBS (HyClone), B-27, 1% penicillin and streptomycin (Invitrogen), and 1% l-glutamine (Invitrogen) on poly-l-lysine-coated (Sigma-Aldrich) coverslips in 24-well plates. Culture media is changed to NB supplemented with B27 at 4 d in vitro (div). Cells are maintained at 37°C, 5% C02, 95% humidity; medium is changed weekly. Neurons cultured for 14 days in vitro are treated with CSF or purified serum IG from individual patients or controls for 1 day then analyzed for anti-NMDAR antibody binding.

[0060] Immunostaining, confocal imaging, and image analysis: Immunostaining, confocal imaging, and image analysis are as previously described, with minor modification (Dalmau 2008; Hughes 2010). To stain surface NMDAR clusters, control or treated neurons are washed in Neurobasal plus B27 and incubated with patient CSF containing anti-NRl antibodies for 30 min, washed and incubated with fluorescently conjugated anti-human secondary antibodies for 30 min, and washed in PBS. Neurons are then fixed in 4% paraformaldehyde, 4% sucrose in PBS, pH 7.4, for 15 min, permeabilized with cold 0.25% Triton X-100 for 5 min and blocked in 5% normal goat serum (Invitrogen) for 1 h at room temperature (RT). Additional immunostaining is performed with primary antibodies, for example, mouse monoclonal anti-NRl CT (1:1000; Millipore Bioscience Research Reagents). Antibodies are visualized after staining with the appropriate fluorescently conjugated secondary antibodies (1:200; Jackson ImmunoResearch). Images are obtained using a confocal microscope (Leica TCS SP2). Images are thresholded automatically using iterative segmentation and the number and area of individual immunostained clusters are determined using interactive software (Bergsman 2006). Clusters with pixel overlap of presynaptic and postsynaptic markers are considered colocalized and thus synaptic (Krivosheya 2008).

Example 2: 7-CI-KYNA effect on antibody binding to surface NMDAR

[0061] Hippocampal neurons cultured for 14 days (Hughes 2010) are cultured for an additional 1 d with dilutions of CSF or serum IG from patients with anti-NMDAR encephalitis in the presence or absence of various concentrations of 7-CI-KYNA, followed by immune-histochemical analyses of surface and total NR1 protein. Patients' antibodies significantly decrease NR1 or NMDAR surface and total cluster density in a titer-dependent fashion, compared with CSF from control patients. The addition of 7- CI-KYNA inhibits patients' antibodies from binding with NMDAR, as shown by a higher cluster density compared to samples with CSF and antibodies from patients. Other approaches for measuring antibody binding to neurons or NMDAR-engineered cell lines are found in the art (e.g., Gleichman 2012; Dalma 2008).

[0062] While certain exemplary embodiments have been described above in detail, it is to be understood that such embodiments are merely illustrative of and not restrictive of the broad invention.

It should be recognized that the teachings of the invention apply to a wide variety of compositions and devices produced from the formulations and compositions described. Persons of skill in the art will recognize that various modifications may be made to the embodiments of the invention described above, without departing from its broad inventive scope. Thus, it will be understood that the invention is not limited to the embodiments or arrangements disclosed, but is rather intended to cover any changes, adaptations or modifications which are within the scope and spirit of the invention as defined by the appended claims.

Example 3: Probenecid increases levels of 4-CI-KYN, 7-CI-KYNA, kynurenine and kynurenic acid [0063] Adult male Sprague Dawley rats (Envigo) were used in the study. A guide cannula was implanted in the left hemisphere dorsal to the PFC for probe implantation. The coordinates for the tips of the cannula dorsal to the PFC were: posterior (AP) = +3.4 mm to bregma, lateral (L) = +0.8 mm to midline and ventral (V) = -1.0 mm to dura, the toothbar set at -3.3 mm (Paxinos & Watson 2001). The final coordinates of the microdialysis probe were: posterior (AP) = +3.4 mm to bregma, lateral (L) = +0.8 mm to midline and ventral (V) = -5.0 mm to dura (Paxinos & Watson 2001).

[0064] The probes of the animals were connected with flexible PEEK tubing to a microperfusion pump. Microdialysis probes were perfused with aCSF, containing 147 mM NaCI, 3.0 mM KCI, 1.2 mM CaCI₂ and 1.2 mM MgCI₂, at a flow rate of 1.5 pL/min. Microdialysis samples were collected for 30-minute periods by an automated fraction collector into mini-vials containing 0.02M formic acid (FA) and 0.04% ascorbic acid in ultrapurified Fl₂0. Basal samples were collected before the administration of vehicle or drug. Animal groups were treated as follows: N=6- L-4-CI-KYN (100 mg/kg ip) + saline ip; N=6- L-4-CI-KYN (100 mg/kg ip) + probenecid (100 mg/kg ip); N=4- vehicle (ip) + vehicle (ip); and N=4- vehicle + probenecid (100 mg/kg ip). All analytes were quantified by H PLC with tandem mass spectrometry (MS/MS) detection using the corresponding stable isotopes labeled (SIL) analytes as internal standards when available. The dialysis samples were divided in a 20 pL aliquots for the analysis of kynurenine (KYN), 4- CI-KYN, kynurenic acid (KYNA), and 7-CI-KYNA.

[0065] Microdialysis results are expressed as a percentage of basal output when possible. Basal output was calculated by dividing each post-dose time point with the average basal output time set as 100%. The level of statistical significance was set at p < 0.05 for all tests.

[0066] For 4-CI-KYN and 7-CI-KYNA, probenecid coadministered with the L-4-CI-KYN led to higher levels. See FIGs. 2-3. KYN and KYNA levels from the vehicle + Probenecid group were significantly higher compared to vehicle + vehicle and L-4-CI-KYN + vehicle groups, and levels from the L-4-CI-KYN + Probenecid group were significantly elevated compared to the vehicle + Probenecid group.

Example 4 [0067] Epileptic activity is induced in rats by delivering NMDAR antibodies into the lateral cerebral ventricles of juvenile Wistar rats via an osmotic pump, according to the technique of Wright et al. Using a depth electrode placed in the CA3 region, spontaneous epileptiform events are observed in the NMDAR antibody-infused animals in vivo. Spontaneous NMDAR antibody-induced epileptic activity in the CA3 region of the hippocampus is reduced in this model following peripheral administration of 4-CI- KYN as compared to a saline control. When either 4-CI-KYN is administered or when 4-CI-KYN and probenecid are co-administered according to the formulations and methods of the present invention, superior anti-seizure efficacy is found in human subjects as compared to non-NMDA specific anti convulsants such as phenobarbital.

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Claims

WHAT IS CLAIMED IS

1. A method of treating autoimmune anti-A/-methyl-D-aspartate receptor (NMDAR) encephalitis, comprising a step of administering to the subject in need thereof a therapeutically effective amount of L-4-chlorokynurenine (L-4-CI-KYN).

2. The method of claim 1, wherein the L-4-CI-KYN is administered as a daily dose ranging from about 50 mg/day to about 3,000 mg/day.

3. The method of claim 1, wherein the L-4-CI-KYN is administered as a unit dose optionally comprising a pharmaceutically acceptable carrier or excipient, wherein the amount of L-4-CI-KYN in the unit dose ranges from about 50 mg to about 1,800 mg.

4. The method of claim 3, wherein the unit dose comprises a pharmaceutically acceptable carrier or excipient.

5. The method of claim 1, wherein the L-4-CI-KYN is administered together with an additional anti- encephalitic treatment.

6. The method of claim 2, wherein the daily dose is 360 mg/day, 720 mg/day, 1,080 mg/day, 1,440 mg/day, 1,800 mg/day, 2,160 mg/day, 2,520 mg/day or 2,880 mg/day.

7. The method of claim 3, wherein the amount of L-4-CI-KYN in the unit dose is 360 mg, 720 mg, 1,080 mg or 1,440 mg.

8. A method of treating autoimmune anti-A/-methyl-D-aspartate receptor (NMDAR) encephalitis, comprising a step of administering to the subject in need thereof a therapeutically effective amount of 7-chlorokynurenic acid (7-CI-KYNA).

9. The method of claim 8, wherein the 7-CI-KYNA is administered as an intrathecal infusion or intracerebral injection.

10. The method of claim 8 or 9, wherein the 7-CI-KYNA is administered as a daily dose ranging from about 2 mg /day to about 40 mg/day.

11. The method of claim 8 or 9, wherein the 7-CI-KYNA is administered as a unit dose optionally comprising a pharmaceutically acceptable carrier or excipient, wherein the amount of 7-CI-KYNA in the unit dose ranges from 2 mg to 40 mg.

12. The method of claim 11, wherein the unit dose comprises a pharmaceutically acceptable carrier or excipient.

13. The method of claim 8, wherein the 7-CI-KYNA is administered together with an additional anti- encephalitic treatment.

14. A method for the treatment of autoimmune anti-A/-methyl-D-aspartate receptor (NMDAR) encephalitis in a subject, the method comprising: assaying a sample from said subject to detect the presence of anti-NMDAR specific antibodies; and administering a therapeutically effective amount of L-4-CI-KYN or 7-CI-KYNA to the subject to treat the autoimmune NMDAR encephalitis, based on the presence of the detected anti-NMDAR specific antibodies in the subject's sample.

15. A method of treating autoimmune anti-A/-methyl-D-aspartate receptor (NMDAR) encephalitis, comprising a step of administering to the subject in need thereof a therapeutically effective amount of L-4-chlorokynurenine (L-4-CI-KYN) in combination with probenecid.

16. The method of claim 15, wherein the L-4-CI-KYN is administered as a daily dose ranging from about 50 mg/day to about 3,000 mg/day and the probenecid is administered as a daily dose ranging from about 250 mg/day to about 2 g/day.

17. The method of claim 15, wherein the L-4-CI-KYN is administered as a unit dose optionally comprising a pharmaceutically acceptable carrier or excipient, wherein the amount of L-4-CI-KYN in the unit dose ranges from about 50 mg to about 1,800 mg and the amount of probenecid in the unit dose ranges from about 250 mg to about 2 g.

18. The method of claim 17, wherein the unit dose comprises a pharmaceutically acceptable carrier or excipient.

19. The method of claim 15, wherein the L-4-CI-KYN and probenecid is administered together with an additional anti-encephalitic treatment.

20. The method of claim 16, wherein the daily dose of L-4-CI-KYN is 360 mg/day, 720 mg/day, 1,080 mg/day, 1,440 mg/day, 1,800 mg/day, 2,160 mg/day, 2,520 mg/day or 2,880 mg/day and the daily dose of probenecid is 500 mg/day, 1,000 mg/day, or 1,500 mg/day.

21. The method of claim 17, wherein the amount of L-4-CI-KYN in the unit dose is 360 mg, 720 mg, 1,080 mg or 1,440 mg.

22. A method for the treatment of autoimmune anti-A/-methyl-D-aspartate receptor (NMDAR) encephalitis in a subject, the method comprising: assaying a sample from said subject to detect the presence of anti-NMDAR specific antibodies; and administering a therapeutically effective amount of L-4-CI-KYN in combination with probenecid to the subject to treat the autoimmune NMDAR encephalitis, based on the presence of the detected anti- NMDAR specific antibodies in the subject's sample.