Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis

Keller, Christian W.; Ruck, Tobias; McHugh, Donal; Pfeuffer, Steffen; Groß, Catharina C.; Korsukewitz, Catharina; Melzer, Nico; Klotz, Luisa; Meuth, Sven G.; Münz, Christian; Nimmerjahn, Falk; Wiendl, Heinz; Lünemann, Jan D.

doi:10.1002/acn3.50935

Cited by 8 publications

(5 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, pharmacogenomics, such as Fc receptor genetic variants, linking to antibody-dependent cellular cytotoxicity, may also be relevant, particularly if antibody titers become limiting. 1,[23][24][25] Although the precise molecular mechanisms that cause the formation of ADA remain to be defined, it is evident that the majority of people produce CD52-specific ADA following alemtuzumab infusion. 7,13 This probably relates to a number of factors that include the dose, dosing schedule, biology of alemtuzumab, CD52 expression profile, and the repopulation kinetics of ADA forming cells and CD52-expressing regulatory subsets.…”

Section: Discussionmentioning

confidence: 99%

Detecting and predicting neutralization of alemtuzumab responses in MS

Saxena

Moore

Jones

et al. 2020

Neurol Neuroimmunol Neuroinflamm

View full text Add to dashboard Cite

ObjectiveTo test the hypothesis that antidrug antibodies (ADAs) against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance.MethodsRecombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding ADAs. Alemtuzumab immunoglobulin G Alexa Fluor 488 conjugate was used in a competitive binding cell-based assay to detect neutralizing ADAs. The assays were used to retrospectively screen, blinded, banked serum samples from people with MS (n = 32) who had received 3 or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month postinfusion.ResultsThe number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. ADA responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred before the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Preinfusion, ADA levels predicted limited, postinfusion lymphocyte depletion.ConclusionsAlthough ADAs to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of lymphocyte depletion and the antidrug response may be of practical value in patients requiring additional cycles of alemtuzumab. ADA detection may help to inform on retreatment or switching to another treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Detecting and predicting neutralization of alemtuzumab responses in MS

Saxena

Moore

Jones

et al. 2020

Neurol Neuroimmunol Neuroinflamm

View full text Add to dashboard Cite

show abstract

“…Total DNA from 1 × 10 6 PBMCs was isolated and FcγRIIIa variants 158 V/F SNPs were analyzed as in reference. 19 DNA isolation and sequencing were conducted at Microsynth, Balgach, Switzerland.…”

Section: Methodsmentioning

confidence: 99%

Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy

Murer,

Brannetti,

Rondeau

et al. 2024

mAbs

View full text Add to dashboard Cite

Novel engineered IL-2 agonists strive to increase the therapeutic window of aldesleukin (human IL-2) by increasing selectivity toward effector over regulatory T cells and reducing dose-limiting toxicities. Here we describe ANV419, an IL-2/anti-IL2 antibody fusion protein designed for selective IL-2 receptor βγ (IL-2 Rβγ) activation by sterically hindering IL-2 from binding to IL-2 Rα. The fusion protein has an IL-2 connected to the light chain complementarity-determining region (CDR) domain of a humanized antibody that binds to IL-2 at the same epitope as IL-2 Rα. Optimization of the selectivity and pharmacological properties led to the selection of ANV419. ANV419 preferentially expands CD8 + T cells and natural killer (NK) cells over T regs and can be safely administered at doses that elicit strong pharmacodynamic effects and efficacy in mouse tumor models. Its anti-tumor efficacy was enhanced when combined with programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors. ANV419 also enhances the NK cell killing capacity and increases tumor growth inhibition when used alongside trastuzumab in a Her-2 + xenograft mouse model. In cynomolgus monkeys, the estimated half-life of ANV419 is 24 h, and doses that induced sustained expansion of effector cells were well tolerated without the severe toxicities typically observed with high-dose IL-2. These data support the clinical development of ANV419 in solid tumors and hematological malignancies as monotherapy and in combination with checkpoint inhibitors or agents that induce antibody-dependent cellular cytotoxicity. ANV419 is currently in Phase 1/2 clinical development and may provide cancer patients with a wider therapeutic window than aldesleukin.

show abstract

“…Finally, after analysis, 15 studies remained that met the inclusion criteria (6,16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

Section: Characteristics Of the Studies Included In The Meta-analysismentioning

confidence: 99%

Risk of secondary immune thrombocytopenia following alemtuzumab treatment for multiple sclerosis: a systematic review and meta-analysis

Sun,

Liu,

Yang

et al. 2024

Front. Neurol.

View full text Add to dashboard Cite

ObjectThe purpose of this study was to evaluate the risk of secondary immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab through a meta-analysis.MethodsWe searched databases including PubMed, Web of Science, OVID and EMBASE for studies reporting changes in platelet levels in MS patients treated with alemtuzumab from their inception until May 2023 and performed a meta-analysis. Information and data were screened and extracted by two researchers. The inclusion and exclusion criteria were established according to the PICOS principle. The obtained data were analyzed using the R software meta package and the quality assessment was conducted using Newcastle-Ottawa Scale (NOS). The causes of heterogeneity were analyzed using subgroup analysis and sensitivity analysis. Publication bias was evaluated using funnel plots and Egger test.ResultsA total of 15 studies were included, encompassing 1,729 multiple sclerosis patients. Meta-analysis of overall secondary ITP in the included studies yielded a pooled rate of 0.0243. The overall incidence of secondary autoimmune events was 0.2589. In addition, subgroup analysis was applied using study regions and study types. The results showed that the incidence rate of secondary ITP in Europe was about 0.0207, while the incidence of autoimmune events (AEs) was 0.2158. The incidence rate of secondary ITP and AEs in North America was significantly higher than in Europe, being 0.0352 and 0.2622. And the analysis showed that the incidence rates of secondary ITP and AEs in prospective studies were 0.0391 and 0.1771. Retrospective studies had an incidence rate of secondary ITP at 2.16, and an incidence rate of AEs at 0.2743.ConclusionThis study found that there was a certain incidence of Immune thrombocytopenia in multiple sclerosis patients after treatment with alemtuzumab. Alemtuzumab may have some interference with platelet levels, and the mechanism may be associated with Treg cells. But due to the absence of a control group in the included literature, we cannot determine the specific impact of Alemtuzumab on platelet levels in patients with MS. Therefore, clinical physicians should perform a comprehensive assessment of the patient’s benefit-to-risk ratio before initiating alemtuzumab.Systematic Review RegistrationInplasy website, DOI number is 10.37766/inplasy2024.3.0007.

show abstract

Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis

Cited by 8 publications

References 16 publications

Detecting and predicting neutralization of alemtuzumab responses in MS

Detecting and predicting neutralization of alemtuzumab responses in MS

Discovery and development of ANV419, an IL-2/anti-IL-2 antibody fusion protein with potent CD8+ T and natural killer cell-stimulating capacity for cancer immunotherapy

Risk of secondary immune thrombocytopenia following alemtuzumab treatment for multiple sclerosis: a systematic review and meta-analysis

Contact Info

Product

Resources

About