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Precision Medicine in Graves' Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal
Larissa C Faustino1, George J Kahaly2, Lara Frommer2
1Department of Medicine, Albert Einstein College of Medicine, New York, NY, United States.
Background:
CD40, a key co-stimulatory molecule expressed on antigen-presenting cells, is genetically associated with a number of autoimmune diseases including Graves' disease (GD). Therefore, recent therapies targeting CD40 have been developed, including the anti-CD40 monoclonal antibody Iscalimab. In a recent pilot study, Iscalimab was shown to induce clinical remission in ~ 50% of GD patients, but the reason why only 50% of GD patients responded is not known. The aim of our study was to test the hypothesis that specific CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes are associated with clinical response of GD patients to Iscalimab.
Methods:
We extracted genomic DNA from the whole blood of 13 GD patients treated with Iscalimab, and genotyped seven CD40 single nucleotide polymorphisms (SNPs) associated with autoimmunity. Additionally, we analyzed CD40 mRNA expression levels in whole blood. The patients' CD40 SNP genotypes and mRNA levels were tested for association with clinical response to Iscalimab.
Results:
Three common haplotypes, designated haplotypes A, B, and C, were identified. Haplotypes B and C were associated with higher CD40 mRNA levels and clinical response to Iscalimab (i.e., patients achieving euthyroidism without need for additional medications), while haplotype A was associated with decreased CD40 mRNA levels and no response to Iscalimab.
Conclusion:
Our data suggest that genetic polymorphisms in the CD40 gene drive its expression levels and response to Iscalimab. Polymorphisms associated with higher CD40 levels are also associated with clinical response to CD40-targeted therapies. These results set the stage to implementing precision medicine in the therapeutic approach to GD.
Insights
Graves' disease patients with specific CD40 gene variations (haplotypes B and C) showed better response to Iscalimab therapy. These CD40 polymorphisms influence gene expression and predict treatment success in autoimmune diseases.
Area of Science:
- Immunology
- Genetics
- Endocrinology
Background:
- CD40 is a co-stimulatory molecule linked to autoimmune diseases like Graves' disease (GD).
- Iscalimab, an anti-CD40 monoclonal antibody, shows promise but only benefits about 50% of GD patients.
- The genetic basis for differential response to Iscalimab in GD is currently unknown.
Purpose of the Study:
- To investigate the association between CD40 single nucleotide polymorphism (SNP) genotypes and haplotypes and clinical response to Iscalimab in GD patients.
- To determine if CD40 genetic variations influence CD40 mRNA expression levels.
- To identify genetic markers predicting Iscalimab treatment efficacy.
Main Methods:
- Genomic DNA was extracted from 13 GD patients treated with Iscalimab.
- Seven CD40 SNPs associated with autoimmunity were genotyped.
- CD40 mRNA expression levels were analyzed, and SNP genotypes/mRNA levels were correlated with clinical response.
Main Results:
- Three common CD40 haplotypes (A, B, and C) were identified.
- Haplotypes B and C were associated with higher CD40 mRNA levels and successful clinical response to Iscalimab.
- Haplotype A was linked to decreased CD40 mRNA levels and lack of response to Iscalimab.
Conclusions:
- Genetic polymorphisms in the CD40 gene influence its expression levels and patient response to Iscalimab.
- CD40 variants associated with higher gene expression correlate with positive clinical outcomes.
- These findings support the implementation of precision medicine for Graves' disease treatment.
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