Dataset Information

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis.

ABSTRACT:

Background and aims

Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing-remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model.

Methods

Anti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters.

Results

We show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice.

Conclusion

Collectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS.

SUBMITTER: Bogie JF

PROVIDER: S-EPMC7443992 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis.

Bogie Jeroen Fj JF Grajchen Elien E Wouters Elien E Broux Bieke B Stinissen Piet P Van Wijmeersch Bart B Hendriks Jerome Ja JJ

Therapeutic advances in chronic disease 20200821

<h4>Background and aims</h4>Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing-remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery ...[more]

PMID: 32913622

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Project description:Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder with typical onset in the 5th- 6th decade of life. The hypothesis of an autoimmune origin of ALS receives less attention today, but immunological phenomena still seem to be involved and mechanisms such as protective autoimmunity may be important. Detection of antibodies against a variety of gangliosides has been repeatedly described in ALS-patients by several authors, but widely differing frequencies and titres have been reported. Therefore, we investigated the presence of six common antibodies with a commercially available test panel for GA1, GM1, GM2, GD1a, GD1b and GQ1b in a large group of clinically well-characterized ALS patients and compared them to a collective of 200 healthy blood donors.IgG and IgM antibodies to the six gangliosides asialoGM1 (GA1), GM1, GM2, GD1a, GD1b, GQ1b were determined by GanglioCombi ELISA in sera of 84 ALS patients. Results were expressed as a %-ratio of a highly positive control and categorized as negative (<30%), borderline (30-50%), moderately (50-100%) and strongly positive (>100%). The values obtained from 200 Swiss blood donors served as a reference group.In twenty-two (26.2%) ALS-patients elevated anti-ganglioside antibodies could be detected: Taking all subspecific antibodies together, IgG antibodies were found in 9/84 (10.7%) and IgM in 15/84 (17.9%) patients. There was no correlation between age, gender, site of onset or survival and anti-ganglioside-positive/-negative titres in ALS-patients. No statistically significant difference in the frequency of anti-ganglioside antibodies compared to the group of healthy blood donors was found.Even with this more comprehensive approach, anti-ganglioside antibody frequencies and patterns in our ALS cohort closely resembled the values measured in healthy controls. In accordance with other studies, we did not observe any association of a distinct ALS phenotype with elevated anti-ganglioside antibodies or an impact on survival.

Project description:IntroductionLymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing-remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb.MethodsTwo first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12 mg) and SC (12, 36, and 60 mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60 mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4 years.ResultsGatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12 months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0-7.5 days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow's disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator.ConclusionsThese data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs.Trial registrationNCT02282826, NCT02977533, NCT02313285.

Dataset Information

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis.

Background and aims

Methods

Results

Conclusion

Publications

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis.

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