Genetics of the response to alemtuzumab


Alemtuzumab kills cells due to depletion via the antibody binding cells such as natural killer cells to attach to the antibody and release toxic molecules. They attach by molecules called the Fc receptor that bind to the tail or the Fc region of the antibody. There are genetic variants of the Fc receptors that are accociated with good or poor binding to immunoglobulin G one. Alemtuzumab and rituximab are IgG1 and it is known that variants in Fc can affect the action. Does this occur in MS. Well the answer is no.

However we sort of knew this already as this study is not the first to look at this.Another good literature search ? and a really good review eh, as they missed this one.. ……… Should have gone to SpeckieSavers:-). Hope they don’t their science as good as their literature review 🙁

Lin TS, Flinn IW, Modali R, Lehman TA, Webb J, Waymer S, Moran ME, Lucas MS, Farag SS, Byrd JC. FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia. Blood 2005 105:289-291

In this new study the find people with variants in the Fc receprot but these variants are not associated with lack of response, when they looked. I guess not that surprising as 40% carry the FcRG3 associated with a poor response and ~30% had the FCGR2A poor response variant but there are not that many people who do not deplete cells, based on published data, and there was no data on lymphocyte depletion. However we do see variation in response to alemtuzumab so what is it?

Impact of FcγR variants on the response to alemtuzumab in multiple sclerosis. Keller CW, Ruck T, McHugh D, Pfeuffer S, Gross CC, Korsukewitz C, Melzer N, Klotz L, Meuth SG, Münz C, Nimmerjahn F, Wiendl H, Lünemann JD. Ann Clin Transl Neurol. 2019 Nov 4. doi: 10.1002/acn3.50935. [Epub ahead of print]

Allelic variants of genes encoding for the Fc gamma receptors IIIA and IIA have been associated with the clinical response to cell-depleting antibodies in lymphoma patients. Here, we tested the hypothesis that FCGR3A and FCGR2A high-affinity polymorphisms predict clinical outcomes to alemtuzumab therapy in 85 patients with relapsing-remitting multiple sclerosis. No differences in clinical and MRI-based efficacy parameters, the development of severe infusion-associated reactions and secondary autoimmune diseases during a 2 year follow-up was observed based on FCGR3A or FCGR2A polymorphisms. This study does not support the use of FCGR genetic variants to predict clinical outcomes to alemtuzumab.

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  • So it is complement mediated lysis, then? Or is the amount of antibody high enough that a poor binder still associates long enough to stimulate cell mediated lysis?

    • You are probably right on both counts. The complement role got dismissed because of mouse work, but many mouse strains are comlement deficieient on not sufficient

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