The human immune system takes apart microbial pathogens and manufactures antibodies to a variety of sites on the microbe, honing its response as the infection progresses. Nearly 40 years ago, scientists became able to create antibody-producing cell lines that did not die, and could produce an infinite amount of antibodies of one type. So, if you can figure out which are the most effective antibodies at fighting an infection, this system allows you to produce as many of them as you want, in cell cultures or other platforms. ZMapp is a mix of 3 different monoclonal antibodies. The owner of ZMapp used tobacco plants to grow the antibodies. This is a clever approach, since tobacco plants grow rapidly. But for reasons not known to me, the manufacturer could not or would not scale up for rapid production.
But maybe ZMapp does not have the optimal choice of antibodies. Maybe more than 1, or more than 3 antibodies, are needed. Maybe certain antibodies must work together, and so specific combinations are needed. This is not clear to scientists.
Furthermore, the best antibodies would be designed with the newest version of the pathogen in mind, based on blood from victims who survived. ZMapp's 3 antibodies came from older Ebola Zaire strains. For reasons unknown to me, the US military appears to have a lock on the newest strains, and is not sharing them.
Finally, use of monoclonal antibodies, or of plasma products (which were used for most of the US Ebola survivors), has its own set of sometimes very serious side effects. This paper discusses adverse effects of monoclonals. Plasma products are best known for transmitting viruses, but can have other problems as well. Over thirty years ago, as an intern, I received Hepatitis B immune globulin (one such product) and developed hepatosplenomegaly, lymphadenopathy and six months of fatigue.
From Reuters:
A group of scientists including three Nobel laureates in medicine has proposed that U.S. health officials chart a new path to developing Ebola drugs and vaccines by harnessing antibodies produced by survivors of the deadly outbreak.
The proposal builds on the use of "convalescent serum," or survivors' blood, which has been given to at least four U.S. Ebola patients who then recovered from the virus. It is based on an approach called passive immunization, which has been used since the 19th century to treat diseases such as diphtheria but has been largely surpassed by vaccination...
So, approximating more of a 'cow pox' vs small pox approach?
ReplyDeleteThat isn't what I meant to imply. Monoclonal antibdies have enormous promise for treating a range of disorders, but they also have sometimes severe advere effects that are not always anticipated or well understood.
ReplyDeleteYet they are a potentially effective drug when there are no drugs. The apparent effectiveness of the plasma transfusions given to most US Ebola vicitms , which are thought to work because they are polyclonal antibody preparations, suggests that the right monoclonals would be even more effective.
Here is an article about the problems with MAbs at this point in time:
Nat Rev Drug Discov. 2010 Apr;9(4):325-38. doi: 10.1038/nrd3003. Epub 2010 Mar 22.
The safety and side effects of monoclonal antibodies.
Hansel TT1, Kropshofer H, Singer T, Mitchell JA, George AJ.
Author information
1Imperial Clinical Respiratory Research Unit, St Mary's Hospital, Paddington, London, UK. t.hansel@imperial.ac.uk
Abstract
Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases, as well as a range of new indications. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies. In addition, there are numerous adverse effects of mAbs that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity. In March 2006, a life-threatening cytokine release syndrome occurred during a first-in-human study with TGN1412 (a CD28-specific superagonist mAb), resulting in a range of recommendations to improve the safety of initial human clinical studies with mAbs. Here, we review some of the adverse effects encountered with mAb therapies, and discuss advances in preclinical testing and antibody technology aimed at minimizing the risk of these events.
So is it fair to assume that there's a great deal of risk for developing some terrible disease as a result of being treated for Ebloa in this way? If so then, considering that these mAbs are similar to in that their non-target effects are--at best--poorly understood in just a fraction of the population, one could postulate that for that reason alone there will be a surge of cancer and autoimmune disorders, perhaps even brain disorders, of no readily apparent cause that are simply a negative side effect of a drug that everyone is all but forced to take while being promised that it's safe?
ReplyDeleteGee, that's going to cost a lot of money.
Oh, and it's going to require people to buy and consume many chemicals (which they are all but forced to take and promised are at least mostly safe) from who?
So what you're saying is that every crazy hippy mom on a soap box being ostracized for refusing to vaccinate her child is doing so--obviously with the child's best interests in mind--in accordance with the correct medical opinion (in some cases at least) given the child's risk of contracting the disease vs. their potential risk of becoming sicker than they would have been had they caught the disease they were being vaccinated for, as well as in accordance with the results and conclusions of a large portion of the work that you've done in your career?
I wish I knew what's going on that would be more relevant to me and my body! May God have mercy on their souls... He isn't so kind to folks that harm others after death as He is in life...
:)
Not sure I understand you.
ReplyDeleteThere are MABs, which have risks, but less than a 70% death rate, for sure. The risk increases with more doses; hopefully, one dose will do it.
The there are blood products. cleaner now than when I was an intern, that have a different set of risks, also considerably less than a 50% or 70% case fatality rate.
When you have a better solution, you switch. But these products can be produced relatively quickly, compared to new drugs and even vaccines.
What I was trying to say, in essence, is that regardless of the cost/benefit analysis, use of these mAbs in a given population set will result in a certain percentage of people within that set experiencing serious, long term side effects.
ReplyDeleteI was trying to highlight similarities between mAbs and vaccine antigens. A "better solution" to the flu vaccine might be simply to risk contracting influenza; conversely, the "best solution" to having Ebola is probably mAbs.
I was also trying to point out that if components of vaccines have the potential--in a small subset of the human race--to cause long term side effects, they'll likely have a similar if not more likely potential to cause such serious conditions as you've mentioned (here and else where) as potentially resulting from these drugs.
Brevity poignancy both frequently elude me.