An Interesting "Off Target" Inference for a Long Acting Monoclonal Antibody for Treatment of Elevated LDLs.

Recently I wrote about my physician's application to my insurance company for a dose of inclisiran (Leqvio), a single dose of which is an RNA drug designed to interfere with PCSK9 induced elevated LDL.

My Cardiologist Is Applying to my Insurance Company to See if I Can Have a $6,500 Injection.

I have also come to understand that the aortic stenosis with which I've been diagnosed is probably genetic in origin, since three of my six aunts, as well as my mother, suffered from valvular heart disease (which aortic stenosis is):

Rheumatic Fever Is An Autoimmune Syndrome Leading to Heart Disease: Strep Throat and Antibiotic Access.

My three aunts who had valvular heart disease all died from it, my mother, by contrast, died from a brain tumor, apparently occupationally related.

To my surprise, a note came back from my insurance company approving me not for inclisiran but for evolocumab (Repatha), which is an equally expensive monoclonal antibody drug.

Both drugs work, mechanistically, by interfering with the PCSK9 system which is involved with degrading LDL receptors on a cellular level.

I have never taken a monoclonal antibody drug, but I am well aware from peripheral aspects of my own scientific work that monoclonal antibodies can, and often do, trigger immune responses, "antidrug antibodies." Since it appears, by inference, that I have a problematic HLA-DRB1 DR4 allele (the suspected Caucasoid mutant chromosome 6) that leads to rheumatic heart disease upon development strep throat that goes untreated (I had an incidence of this that was treated but with a significant delay), I wondered about possible immune responses to evolocumab that might trigger this gene.

I have satisfied myself, as of this evening, that my concern is unwarranted. Evolocumab is a humanized antibody that is known to not trigger immunogenic responses, and I have located no evidence of any interaction with activating this particular receptor.

My concern, it appears, was driven by my very limited understanding of immunology; I'm getting a nice education.

But, here is an interesting note relevant perhaps not to the deaths of my aunts, but to the death of my mother (at the age of 51):

Singh, K., Foster, M.W., Violette, M.J. et al. A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8+ infiltration in glioma. Sci Rep 15, 37112 (2025)

The paper is open source, as all papers in Scientific Reports are. There's no need therefore to dig into it here.

I have convinced myself that my risk of glioma is probably not significant from a genetic standpoint, although it would be interesting (but clearly impossible) to understand the genomes of all the people who worked in the factory where my mother was employed who developed brain tumors. Not everyone developed brain tumors; only some of them did.

In any case, the paper suggests that evolocumab transits the blood brain barrier, and that PCSK9 is involved in the etiology of glioma.

Thus, taking the evolocumab injection might have a beneficial side effect should I be wrong about the etiology of my mother's fatal disease, that, despite my happy whistling in the dark, I do face risk. (The superfund status of my mother's old plant involved halogenated species which are now ubitiquous in the environment, including my well water, but at very low levels.)

I can't complain. I've outlived my mother by a significant number of years.

Cool.

I'll take the drug, and do so enthusiastically.

I'll find out tomorrow if I need heart surgery. I'm prepared for the discussion with my doctor.

I am very fortunate that I can understand drugs beyond the disclaimers in the TV ads. I don't need no stinking advertising jingle played over videos of partying people.

Enjoy the upcoming day.