Precision Medicine in Graves' Disease: CD40 Gene Variants Predict Clinical Response to an Anti-CD40 Monoclonal Antibody.

Larissa C Faustino,Lara Frommer,Erlinda Concepcion,Mihaela Stefan-Lifshitz,Yaron Tomer,George J Kahaly

doi:10.3389/fendo.2021.691781

Abstract

BackgroundCD40, 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.MethodsWe 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.ResultsThree 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.ConclusionOur 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.

Highlights

Graves’ disease (GD) is one of the most common organ-specific autoimmune diseases affecting 1% to 2% of the adult population in the US [1, 2]
We have previously identified a functional CD40 C/T single-nucleotide polymorphism (SNP) that was associated with GD [14, 23]
Our cohort included 13 GD patients treated with Iscalimab (two patients from the original cohort [22] were not available for testing)

Summary

Introduction

Graves’ disease (GD) is one of the most common organ-specific autoimmune diseases affecting 1% to 2% of the adult population in the US [1, 2]. Even in patients that achieved biochemical euthyroidism with T4 replacement (after thyroid ablation) many still report symptoms and reduced quality of life [9,10,11]. There is a need for new curative therapies for GD targeting the autoimmune mechanisms underlying the disease. One such novel and exciting new therapy has been the development of a monoclonal antibody, Iscalimab (CFZ533), which targets the co-stimulatory molecule CD40 [12, 13]. 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

Objectives

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Results

Conclusion