Assessment of Bezlotoxumab Immunogenicity

Montgomery, Diana; Matthews, Randolph P.; Yee, Ka Lai; Tobias, Lori; Dorr, Mary Beth; Wrishko, Rebecca E.

doi:10.1002/cpdd.729

Cited by 3 publications

(2 citation statements)

References 15 publications

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“…In patients enrolled in the MODIFY trials and receiving placebo, endogenous serum antibodies against toxin B were protective against rCDI, whereas endogenous serum antibodies against toxin A were not, this being in line with the protective effect observed for bezlotoxumab but not for actoxumab [58]. Staying on the topic of endogenous antibiotics, the immunogenicity potential of bezlotoxumab has been shown to be low, and no development of treatment-emergent anti-bezlotoxumab antibodies was observed in patients enrolled in registrative studies [59]. With regard to the timing of bezlotoxumab administration, efficacy in preventing rCDI was not influenced by the time of administration with respect to the onset of antibiotic therapy (i.e.…”

Section: Efficacy Of Bezlotoxumab In Phase 3 Rctssupporting

confidence: 54%

Bezlotoxumab for Preventing Recurrent Clostridioides difficile Infection: A Narrative Review from Pathophysiology to Clinical Studies

et al. 2020

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Clostridioides difficile infection (CDI) and recurrent CDI (rCDI) remain associated with a reduction in the patients' quality of life and with increased healthcare costs. Bezlotoxumab is a monoclonal antibody against toxin B of C. difficile, approved for prevention of rCDI. In this narrative review, we briefly discuss the pathophysiology of CDI and the mechanism of action of bezlotoxumab, as well as the available evidence from investigational and observational studies in terms of efficacy, effectiveness, and safety of bezlotoxumab for the prevention of rCDI. Overall, bezlotoxumab has proved efficacious in reducing the burden of rCDI, thereby providing clinicians with an important novel strategy to achieve sustained cure. Nonetheless, experiences outside randomized controlled trials (RCTs) remain scant, and mostly represented by case series without a control group. Along with the conduction of RCTs to directly compare bezlotoxumab with faecal microbiota transplantation (or to precisely evaluate the role of their combined use), further widening our post-marketing experience remains paramount to firmly guide the use of bezlotoxumab outside RCTs, and to clearly identify those real-life settings where its preventive benefits can be exploited most.

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Section: Efficacy Of Bezlotoxumab In Phase 3 Rctssupporting

confidence: 54%

Bezlotoxumab for Preventing Recurrent Clostridioides difficile Infection: A Narrative Review from Pathophysiology to Clinical Studies

et al. 2020

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“…Furthermore, a study in MHC class II knockout mice and CD4 ϩ T-cell knockout mice found that protection from rCDI is dependent on antitoxin antibody formation and requires MHC cass II genes (29). Bezlotoxumab has low immunogenicity potential (30), suggesting that the association between specific HLA alleles and response to treatment is not related to an immunogenic response against bezlotoxumab itself, but rather a host response against infection that becomes important specifically in subjects administered treatment. However, conditional analysis indicates that the association with HLA alleles may be largely driven by the rs2516513 locus, rather than by an independent association driven by a particular HLA allele.…”

Section: Discussionmentioning

confidence: 99%

Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment

Shen

Mehrotra

Dorr

et al. 2020

mSphere

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Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II). IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.

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Clinical Immunogenicity Risk Assessment Strategy for a Low Risk Monoclonal Antibody

Kernstock

Sperinde²,

Finco³

et al. 2020

AAPS J

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Assessment of Bezlotoxumab Immunogenicity

Cited by 3 publications

References 15 publications

Bezlotoxumab for Preventing Recurrent Clostridioides difficile Infection: A Narrative Review from Pathophysiology to Clinical Studies

Bezlotoxumab for Preventing Recurrent Clostridioides difficile Infection: A Narrative Review from Pathophysiology to Clinical Studies

Genetic Association Reveals Protection against Recurrence of Clostridium difficile Infection with Bezlotoxumab Treatment

Clinical Immunogenicity Risk Assessment Strategy for a Low Risk Monoclonal Antibody

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