Sunday, 22 September 2013

CD52, alemtuzumab and sperm counts

Alemtuzumab and sperm counts is a non-issue. #MSBlog #MSResearch

"There have been several queries on this blog about whether, or not, alemtuzumab affects male fertility. This is because of the protein that alemtuzumab targets on white blood cells is also present on sperm. The first study below shows that alemtuzumab can target sperm. But this study is not realistic in that it is done in a laboratory, i.e. in a test tube. In the body sperm are protected from antibodies, and certain chemicals, by the blood-stestis-barrier, which is similar to the blood-brain-barrier. Unless this barrier is damaged or leaky antibodies are unlikely to get into the testes in sufficient quantities to affect sperm counts or function. In addition, alemtuzumab is given as well defined short courses; 5 days in year 1 and 3 days in year 2 and subsequent years in MS. Alemtuzumab is therefore not around long enough to affect sperm function."



"The proof is in the eating of the pudding, we have had several male MSers who have been treated with alemtuzumab who have gone onto have children who are healthy and well. I would urge you to wait until more detailed data on this issue is presented at ECTRIMS. I promise to post the results as soon as I can. In my opinion the sperm issue is a non-issue." 

"The second study below is simply a hypothesis paper suggesting that scientists target CD52, and related proteins, on sperm as an immunological target for a male contraceptive. This idea is barmy; simply because CD52 is present on all white cells and if the immune, or vaccine, strategy worked then all male recipients who received it are likely to develop a severe leukopenia (low white cell count) as the antibodies would also target white cells and put them at risk of infections. Who would sign-up for a study for a contraceptive vaccine with the potential to cause a leukopenia? The other reason why it is barmy is that if you induce an immune response against your sperm, or testes, to lower the sperm count you may not be able to reverse it and hence you will be left with permanent infertility. The principle behind contraception is reversible infertility not permanent infertility."
"The final paper that refers to infertility in male bone marrow recipients. In this context alemtuzumab is usually given in conjunction with other conditioning treatments that damage the testes. This study is important and demonstrates why you simply can't extrapolate what is in the oncology, or transplant, literature to the field of MS. I have noted that a lot of readers have been reading about the safety profile and side effects of alemtuzumab in leukemia and assuming that this is the profile in MS. It is not. Firstly, the leukaemia patients are much older and much sicker than MSers; in other words they have lots of other problems that puts them at risk of infections and complications of treatment. Secondly, the dose of alemtuzumab that is used to treat leukemia is much larger than the doses used to treat MS. Leukaemia patients get over 1,000mg in a year compared to 60mg in year and 36mg in year 2 for MSers. Thirdly, leukemia patients tend to have a high cell or tumor burden that puts  them at risk of cell lysis syndrome. Alemtuzumab works like a heat-seeking missile and binds to CD52 on the surface of white blood or leukemia cell, it then activates other proteins in the blood that punch a hole in the cell causing it to release its contents and die. As cells burst they release their active molecules that are responsible for the infusion reactions. The more cells that burst the more active molecules are released the greater the infusion reaction. When this occurs in leukemia patients the number of cells bursting is much larger than what occurs in MS hence the occurrence of serious and life threatening infusion reactions are almost exclusive to the leukemia population."
"My advice to readers of this blog is not to read about any of the side effects that occur in alemtuzumab-treated leukemia, cancer and transplant patients, they are simply not relevant to MS. You need to focus on what happens in MSers who receive this drug; the side effect profile in MSers is very different and manageable."

Focarelli et al. A sialoglycoprotein, gp20, of the human capacitated sperm surface is a homologue of the leucocyte CD52 antigen: analysis of the effect of anti-CD52 monoclonal antibody (CAMPATH-1) on capacitated spermatozoa. Mol Hum Reprod. 1999;5(1):46-51.

Background: There are concerns  that alemtuzumab may affect sperm function.


Methods: In this study they performed N-terminal sequence analysis of gp20, a 20 kDa sialoglycoprotein on the human sperm surface previously identified by radiolabelling of the sialic acid residues of sperm surface. 

Findings: They found 100% identity with the N-terminus of CD52, an antigen expressed on almost all human leukocytes. They show that, like CD52, gp20 behaves as a glycosylphosphatidylinositol (GPI)-anchored protein and that anti-gp20 antiserum reacts with an antigen on leukocytes of the same molecular weight as CD52. Using CAMPATH-1 or alemtuzumab, the monoclonal antibody against CD52, in fluorescent staining of capacitated spermatozoa, Western blot analysis and the zona-free hamster egg penetration test, they found that the effect of this antibody was different from that of our anti-gp20. Western blot analysis revealed a well-defined 20 kDa band with anti-gp20, whereas a 14-20 kDa band was detected with CAMPATH-1. Anti-gp20 stained the equatorial region of the sperm head, whereas CAMPATH-1 stained the tail in immunofluorescence analysis of capacitated spermatozoa. A dose-dependent inhibitory effect was seen with CAMPATH-1, similar to that previously detected with anti-gp20, in a zona-free hamster egg penetration test. However, with CAMPATH-1 agglutination of motile spermatozoa was detected, and this was not present with anti-gp20. 

Conclusions: This suggests that the epitopes recognized by the two antibodies are different.

Kirchhoff C, Schröter S. New insights into the origin, structure and role of CD52: a major component of the mammalian sperm glycocalyx. Cells Tissues Organs. 2001;168(1-2):93-104.

The sperm glycocalyx represents the primary interface between the male gamete and its environment, and gamete interaction inevitably involves interaction with this structure. Thus, it has potential significance as a target for antibodies that inhibit sperm function. Still, little is known about the components and biological role of the sperm glycocalyx. Despite the apparent complexity of the sperm membrane, surface carbohydrate labelling experiments show a high selectivity suggesting that carbohydrate side chains of CD52, an unusually short, bipolar glycopeptide of epididymal origin, form major components of the sperm glycocalyx in all mammalian species investigated. Acquisition of the highly sialylated, lipid-anchored CD52 antigen is one of the few well-defined modifications that occur to the sperm membrane during epididymal passage. It would explain changes in lectin-binding patterns and also the remarkable surface charge differences occurring during epididymal transit, most probably attributable to its terminal sialic acid residues. CD52 seems to be immunodominant on human spermatozoa, and antibodies directed against it can agglutinate and completely immobilize human sperm in the presence of complement. Expression of the same peptide backbone in lymphocytes had largely discounted its consideration as a candidate for contraceptive development. However, the recent proof of male-specific modifications indicates the feasibility of this approach.

Kyriacou et al. Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative transplantation for haematological malignancies..Bone Marrow Transplant. 2003 Jan;31(1):45-50.

Background: Most bone marrow transplant recipients are infertile due to reversible or irreversible testicular failure. However, little is known about the gonadotoxic potential of the newly introduced nonmyeloablative transplants. 

Objective: They undertook a 24-month longitudinal study in a cohort of 32 recipients of nonmyeloablative transplantation to test whether the combined regimen of fludarabine, melphalan and CAMPATH-1H can induce damage to germ cell (GC) and Leydig cell (LC) compartments. 

Methods: Testicular function was assessed immediately prior to transplantation and at four time points post-transplant to compare hormonal levels before and after the procedure. Two other groups treated with BEAM- and TBI-related regimes were also included in the study group for comparative purposes. GC function was assessed by measuring basal serum follicle stimulating hormone (FSH). LC function was assessed by measuring basal luteinising hormone (LH) and testosterone (T) levels. LC reserve was assessed by measuring the T/LH ratio. 

Results: As a group, patients who received a non myeloablative transplant sustained severe damage to the GC compartment, as evident from a substantial elevation in the FSH level post-transplant (12 IU/l vs 18.4 IU/l, P<0.001). Similar to the GC injury, patients as a group sustained significant damage to the LC compartment following the transplant (5.4 IU/l vs 9.6 IU/l, P<0.001). In general, patients had reduced LC reserve post-BMT, as evident from a diminished T/LH ratio (2.6 pretransplant vs 1.6 post-transplant P=0.05). Patients who received a nonmyeloablative transplant had a similar effect on the GC and LC compartments compared to those who had a BEAM autograft. On the other hand, patients who received a TBI-based transplant sustained more damage to their GC and LC compartments compared to those who received a nonmyeloblative transplant; however, this was not statistically significant (P=0.09). 

Conclusions: Our data suggest that this type of regimen is potentially gonadotoxic and consideration should be given to fertility counselling and testosterone replacement therapy post-transplant.

CoI: multiple

13 comments:

  1. It is called the blood testis barriwr not blood sperm barrier

    ReplyDelete
  2. Blimey, Don Giovannoni! I return from my lengthy summer travels (it was great, thanks for asking) only to see you’re still advocating the use of unknown and highly powerful chemo toxics. Not only that, you’re stating that proven side-effects attributed to alemtuzumab should be disregarded by MSers. Wow, what a world we live in.

    We have no long-term reporting on how alemtuzumab is messing up the biology of MSers, therefore, it seems most logical and prudent to read about how it has affected oncology subjects and deduce the probable impacts this drug may have on MS sufferers cajoled into taking alemtuzumab. Your anecdotal reporting on how you perceive patients in your care are doing after taking alemtuzumab is cute, but it’s hardly scientific. The point is alemtuzumab is a dangerous concoction, one that has led to brain PML complications and fatalities; yet your analysis of alemtuzumab is worryingly simplistic, almost like a kid taking sweeties. Is this responsible? Don’t you feel your blog is becoming a subjective portal that fails to objectively balance the risks of taking alemtuzumab? Don’t you think you’ve crossed a little too severely into the profitable pharmacopeia dark side?

    Look, Don Giovannoni, you are not a bad man. You’re a good man that is unwilling to see the bigger picture. You’re kind of like Tony Blair when he was trying to convince us about participating in an illegal foreign war by making an issue about non-existent weapons of mass destruction. Blair had convinced himself he was doing the right thing, but you and I know he was wrong. He still says he was right, but let’s not kid ourselves. He got it wrong, though he did become a multimillionaire out of it.

    I have no idea what new things have happened while I was away, though I take it you haven’t discovered why MS happens? You see, until you crack that one you haven’t really got a case for propagating the utilisation of alemtuzumab to cure MS, have you? The long-term affects alemtuzumab may have on the patient’s future progeny may not materialise until thirty years later. By that time alemtuzumab may be about as trustful as WMDs.

    ReplyDelete
    Replies
    1. Oh, Dre. How we missed thee! Let us know when you're going away again.

      Delete
    2. I have no idea what new things have happened while I was away

      Maybe read and enjoy:-) Hope the new microbiome works?

      Delete
    3. Dre

      Why don't you formulate a few concise questions for the Question time at ectrims.

      Delete
    4. Last week David Cameron and this week Tony Blair

      Delete
  3. Dr Dre what a beautifully written comment! I whole heartedly agree.

    Prof Giovannoni- for the avoidance of doubt, can you please declare, in total, how much money you have personally received from Genzyme for all of your consulting work with regards to Alemtuzumab? This would enable us to better judge your potential conflicts of interest.

    ReplyDelete
    Replies
    1. ProfG has declared conflicts of interest,if he has received remuneration for providing consultation, which would be appropriate, then that should be confidential between himself and Sanofi.

      What he does with that money such as declare Tax as a personal fee, give it to the University etc, support education, research or other activities, is not something we discuss even in professional circles

      ProfG has indeed consulted for Sanofi/Genzymne just as he has done for viruallyallMS-associated companies. This is declared. Take it that he is conflicted, just as he says so.

      "We have no long-term reporting on how alemtuzumab is messing up the biology of MSers"....When papers are published in this area then we will comment on them.

      "Don’t you feel your blog is becoming a subjective portal that fails to objectively balance the risks of taking alemtuzumab?"

      You need to do your homework and make an informed choice.We are not a prescription service and it is clear that CAMPATH-1H has significant risk...likewise so does sticking you head in the ground and pretending every thing is rosey.

      Don’t you think you’ve crossed a little too severely into the profitable pharmacopeia dark side?

      Delete
  4. Love him or hate him, I do think that Dre makes this blog a more entertaining and thoughtful resource of information. I hate to say it, I almost missed his elegant musings. You should have your own section on this blog. Like a yin and yang of MS reporting.

    Is Prof G and MouseDoc willing to collaborate to make this happen? Dre, will you be willing?

    ReplyDelete
    Replies
    1. Dr Dre is completely free to set up his/her own blog. I don't think having a naysayers/doom mongers corner on this blog would add anything useful. I suspect most of our visitors here would agree.

      Delete
    2. Lord above! What is this blog coming to!?!?! Why is Dr. Dre being celebrated? Why is MouseDoc asking Dre to formulate a few concise questions for the Question time at ectrims.?

      I would love to know why some followers hold Dre in high regard? The bloke hasn't ever contributed anything useful. He's just a smart-ass. He's like that kid in school that would disrupt lessons to get attention, and then left thinking he was too cool and clever to be there in the first place.

      Dre may have fans on this blog, but I'm not one of them. I hope he has another lengthy holiday planned soon, preferably in a destination with no internet connection.

      Delete
    3. Well said Anon 4:26:00, Dr Dre is not only a smart-ass, but a pain-in-the-ass.

      Thanks Prof G for taking the time to highlight the differences between the use of Campath in cancer and Lemtrada in MS; I am sure a lot of us were getting alarmed with what we were finding on the web when searching under alemtuzumab.

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.