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

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

Background:

Multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML) are disorders that affect the central nervous system (CNS). The CNS includes the brain, spinal cord, and optic nerves. Both diseases can cause muscle weakness and impair vision, speech, and coordination. Researchers are working to better understand how MS and PML affect the CNS.

Objective: To test whether an experimental radioactive tracer (minibody) can help positron emission tomography (PET) scans detect certain immune cells in the CNS of people with MS and PML.

Eligibility:

People aged 18 years and older with MS or PML.

Design:

Participants will come to the clinic for at least 3 visits over 4 to 6 weeks.

Participants will undergo testing. They will have a physical and neurological exam. They will have blood tests and tests of their heart function. They will have a magnetic resonance imaging (MRI) scan of the brain. They may have a spinal tap: Their lower back will be numbed, and a needle will be inserted between the bones of the spine to withdraw fluid from around the spinal cord.

Minibody is given through a tube with a needle placed in a vein in the arm. This takes 5 to 10 minutes. Participants will have heart function tests before and after receiving the minibody.

Participants will return the next day for the PET scan. They will lie on a table that moves through a doughnut-shaped machine. This scan will take about 1 hour.

Participants with PML may opt to repeat the minibody infusion and the PET scan within 6 months.

Study Overview

• Status: Recruiting
• Conditions: Multiple Sclerosis; Progressive Multifocal Leukoencephalopathy
• Intervention / Treatment: Drug: 89 Zr-Df-crefmirlimab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Daniel S Reich, M.D.; Phone Number: (301) 496-1801; Email: reichds@ninds.nih.gov
• Study Contact Backup: Name: Maria I Gaitan, M.D.; Phone Number: (301) 496-1801; Email: maria.gaitan@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	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).
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	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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infiltration of CD8+ T cells in the CNS of adults with MS and PML via PET-CT scans using a minibody with high affinity for CD8+ T cells.	To detect and localize infiltration of CD8+ T cells in the CNS of adults with MS and PML via PET-CT scans using a minibody with high affinity for CD8+ T cells.	Day 1 Study Visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of 89Zr-Dfcrefmirlimab in the participants with CNS disease.	To assess the safety of 89Zr-Dfcrefmirlimab in participants with CNS disease.	At each study visit
For the PML cohort with longitudinal evaluation, effects of immune reconstitution, either spontaneous or facilitated, on 89Zr-Dfcrefmirlimab uptake.	Comparison of SUV before and after immune reconstitution, either spontaneous or facilitated (for participants with optional follow-up imaging).	up to 6 months after first PET/CT scan

Collaborators and Investigators

• Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Daniel S Reich, M.D., National Institute of Neurological Disorders and Stroke (NINDS)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2023
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: May 8, 2023
• First Submitted That Met QC Criteria: May 8, 2023
• First Posted (Actual): May 9, 2023

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 4, 2024
• Last Verified: March 25, 2024

More Information

Terms related to this study

• Keywords: PET Imaging; 89 Zr-Df-crefmirlimab
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Virus Diseases; Infections; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Encephalitis, Viral; Central Nervous System Viral Diseases; Central Nervous System Infections; Infectious Encephalitis; DNA Virus Infections; Slow Virus Diseases; Encephalitis; Polyomavirus Infections; Neuroinflammatory Diseases; Multiple Sclerosis; Sclerosis; Leukoencephalopathy, Progressive Multifocal; Leukoencephalopathies
• Other Study ID Numbers: 10001519; 001519-N

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No