Central Nervous System Uptake of Anti-CD8+ T Cell Minibodies in Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy

Study Description:

This study will obtain pilot data for noninvasive positron emission tomography (PET) imaging of CD8 plus T lymphocytes in two inflammatory central nervous system (CNS) demyelinating diseases, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML), and other neuroinflammatory diseases by characterizing CNS uptake of anti-CD8 plus T cell antibody fragment (aka minibody ) (89Zr-Df-crefmirlimab), an investigational, intravenous PET tracer.

Objectives:

Primary Objective: To detect and localize infiltration of CD8 plus T cells in the CNS of adults with MS and PML via PET-CT (computed tomography) scans using a minibody with high affinity for CD8 plus T cells.

Secondary Objectives: (1) To characterize safety and tolerability of 89Zr-Df-crefmirlimab in the participant population. (2) For the PML cohort with longitudinal evaluation, to determine the effects of immune reconstitution, either spontaneous or facilitated, on 89Zr-Dfcrefmirlimab uptake. (3) To determine whether 89Zr-Df-crefmirlimab uptake profile is disease specific for MS and PML.

Endpoints:

Primary Endpoints: Standardized uptake values (SUV) in different tissue types (lesions, white matter, gray matter, meninges, choroid plexus, as determined from coregistered MRI) in each cohort (MS or PML) by region-of-interest (ROI) analysis.

Secondary Endpoints: (1) Frequency and nature of adverse events; (2) For the PML cohort with longitudinal evaluation, changes in SUV over time. (3) Compare patterns of uptake distribution across PML, MS, and other neuroinflammatory diseases with BBB leakage.

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

Multiple Sclerosis Inclusion Criteria

• Enrolled in the NINDS Natural History Study for MS (protocol 89-N-0045)
• Able to understand, and willing to sign, a written, informed consent document.
• Willing to comply with all study procedures and available for the duration of the study.
• Male or female, aged >=18.
• Diagnosis of MS according to the 2017 revision of the McDonald diagnostic criteria48 (in the presence or absence of a clinical relapse).

PML Inclusion Criteria

• Enrolled in the NINDS Natural History Study for PML (protocol 13-N-0017)
• Able to understand and willing to sign a written, informed consent document
• Willing to comply with all study procedures and available for the duration of the study.
• Male or female, aged >=18.
• Diagnosis of definite PML according to 2013 AAN Consensus Criteria49 or PML-IRIS based on clinical, radiological and laboratory evidence.

Patients with Known or Suspected Neuroinflammatory Diseases and Evidence of Open BBB Inclusion Criteria

-Clinical evaluation suggesting an inflammatory disorder of the central nervous system other than MS or PML. Other confirmed neuroinflammatory disorders may include -MOGAD, NMOSD, Behcet's syndrome, and neurosarcoidosis. Unconfirmed, though

suspected cases of neuroinflammation may also be included.

• Recent brain MRI (within 1 month) with gadolinium enhancement indicating open BBB.
• Able to understand and willing to sign a written, informed consent document.
• Willing to comply with all study procedures and available for the duration of the study.
• Male or female, aged >=18.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Pregnant or lactating.
• Contraindications for MRI gadolinium contrast administration or 3T MRI.
• History of, or current diagnosis with, concomitant medical or clinical conditions that would adversely affect participation in this study.
• Weighs > 350 lb. (158 kg; weight limit for the scanner table) or is unable to fit within the MRI or PET imaging gantry.
• Severe claustrophobia unresponsive to oral anxiolytics.
• Has an alkaline phosphatase level greater than 2x ULN (unless known to have non-liver related disorder) OR AST greater than 1.5 x ULN OR ALT greater than 1.5 x ULN.
• Has a total bilirubin >1.5X ULN, unless known to have elevated bilirubin due to nonliver related disorder or Gilbert s.
• Creatinine clearance < 60 mL/min as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
• For females of reproductive potential: inability to use highly effective contraception for at least one month prior to screening and during study participation.