TY - JOUR
T1 - Precision Medicine in Graves’ Disease
T2 - CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody
AU - Faustino, Larissa C.
AU - Kahaly, George J.
AU - Frommer, Lara
AU - Concepcion, Erlinda
AU - Stefan-Lifshitz, Mihaela
AU - Tomer, Yaron
N1 - Funding Information:
This work was supported in part by grants DK067555 & DK073681 from NIDDK (to YT). The JGU Medical Center, Mainz, Germany has received research-associated funding from Novartis, Cambridge, MA, USA to perform a phase II trial of
Funding Information:
Conflict of Interest: YT, GK, and LFa declare that they submitted a Patent Application (US Provisional Application No: 63/120,514) entitled: “Method for predicting patient response to CD40-targeted therapies” which is related to the current manuscript. YT declares that he also submitted two additional patent disclosures that are not related to the content of this manuscript. YT was previously (January 2015 to June 2017) the PI on a basic research project jointly funded by the Juvenile Diabetes Research Foundation and Pfizer. The current manuscript is not related to that research project. GK consults for Immunovant, USA, Mediomics, USA, Merck, Germany, Novartis, Switzerland, and Quidel, USA.
Publisher Copyright:
© Copyright © 2021 Faustino, Kahaly, Frommer, Concepcion, Stefan-Lifshitz and Tomer.
PY - 2021/6/4
Y1 - 2021/6/4
N2 - 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.
AB - 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.
KW - CD40
KW - Graves’ disease
KW - gene
KW - precision medicine
KW - variant
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U2 - 10.3389/fendo.2021.691781
DO - 10.3389/fendo.2021.691781
M3 - Article
AN - SCOPUS:85108184758
VL - 12
JO - Frontiers in Endocrinology
JF - Frontiers in Endocrinology
SN - 1664-2392
M1 - 691781
ER -
