Mouse Monoclonal Antibodies Generated from Full Length Human Cereblon: Detection of Cereblon Protein in Patients with Multiple Myeloma

Abstract

Immunomodulatory drugs (IMiDs) are profoundly active compounds in the treatment of patients with multiple myeloma (MM). However, despite the fact that treatment with IMiDs has dramatically improved survival for patients with MM, the majority of MM patients develop IMiDs resistance over time. We have found that expression of functional cereblon is required for IMiDs′ action. In addition, it has been reported that cells expressing high levels of cereblon are resistant to proteasome inhibitor, implying that patients with high levels of cereblon should be resistant to proteasome inhibitor. If the above conclusions are correct, cereblon could be considered as a biomarker to determine which standard regimens should be used to treat patients with MM. Unfortunately, the conclusions mentioned above have not been clinically confirmed. In order to confirm these conclusions, we have generated three highly specific mouse monoclonal antibodies (mAbs) against full-length human cereblon. These mAbs can be used to do western blot, immunoprecipitation and immunohistochemistry staining. In addition, their epitopes have been precisely determined and the peptides covering their epitopes completely blocked the antibody binding to cereblon in western blot analysis or in immunohistochemistry staining of MM patients′ specimens.

The Impact of Beta-Catenin and glutathione-S-transferase Gene Polymorphisms on the Treatment Results and Survival of Multiple Myeloma Patients

“…GSTP1 105 variant of this enzyme has less ability for detoxification, therefore the effectivity of cytostatic agents is increased in such multiple myeloma patients. In patients carrying the GSTP1 105Ile homozygous genotype, event-free and overall survival results were reported to be more favourable after alkylating agent or anthracyclin-based treatment [16]. In our cohort, neither GSTP1 105, nor GSTP1 114 polymorphisms had any impact on the treatment results and survival data.…”

“…In patients having GSTP1 105 variant genotype, detoxification process was less active, therefore chemotherapeutical agents can be more effective. In MM patients carrying GSTP1 105Ile homozygous genes, progression-free (PFS) and overall survival results were reported to be more favourable [16].…”

Cereblon gene variants and clinical outcome in multiple myeloma patients treated with lenalidomide

“…Whether these associations may be driven by genetic variations in the CRBN gene remains unknown, as there are currently no clear biomarkers that predict response to lenalidomide therapy. Attempts to quantify cereblon’s utility as a clinical biomarker for IMiDs is ongoing 20–23 . One study found an increased prevalence of mutations in both CRBN and the CRBN pathway impacting CRBN-IMiD interactions in patients with multidrug refractory disease, and subsequently observed conferred lenalidomide resistance in vitro following the functional introduction of these mutations in MM cells 24 .…”