• -

  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).

• - For females of reproductive potential: agrees to use highly effective contraception for at least one month prior to screening and during study participation.

• - Creatinine clearance >= 60 mL/min as estimated by the Cockcroft-Gault equation.

• - Has aspartate transaminase (AST) or alanine transaminase (ALT) levels less than 1.5x ULN.

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.

• - For females of reproductive potential: agrees to use highly effective contraception for at least one month prior to screening and during study participation.

• - Creatinine clearance >= 60 mL/min as estimated by the Cockcroft-Gault equation.

• - Has aspartate transaminase (AST) or alanine transaminase (ALT) levels less than 1.5x ULN.

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, and AST and ALT remain stable.

• - Has a total bilirubin >1.5X ULN, unless known to have elevated bilirubin due to nonliver related disorder or Gilbert s.

Study Description: This study will obtain pilot data for noninvasive positron emission tomography (PET) imaging of CD8+ T lymphocytes in two inflammatory central nervous system (CNS) demyelinating diseases, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML), by characterizing CNS uptake of anti-CD8+ T cell antibody fragment (aka minibody ) (89Zr-Dfcrefmirlimab), an investigational, intravenous PET tracer. Objectives: Primary Objective: To detect and localize infiltration of CD8+ 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+ 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.

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.

Arms

Experimental: Multiple Sclerosis

MS cohort- Three study visits. (1) Baseline; (2) Day 0: MRI brain/spinal cord (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka"PET/CT tracer"); (3) Day 1: PET/CT scan

Experimental: Progressive Multifocal Leukoencephalopathy

PML cohort- Up to five study visits. (1) Baseline; (2) Day 0: MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer"); (3) Day 1: PET/CT scan; (4) Study visit 4 (optional; time-period between study visit 3 and 4 is variable): MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer") following clinical, radiological and/or laboratory-defined immune reconstitution (spontaneous or facilitated); (5) Study visit 5: PET/ CT scan

Interventions

Drug: - 89 Zr-Df-crefmirlimab

an 80 kDa minibody (Mb) with high affinity to CD8 glycoprotein (binding EC50 = 0.4 nM) that is conjugated with deferoxamine (Df) and radiolabeled with the positron emitting radionuclide, Zr-89 (T1/2 78.4 hours).