Wednesday, July 11, 2007

6:25 AM 7/11/2007

Well, well, well. Here I find myself on another flight back home. This trip has been one sleepless adventure and I don't remember ever being so tired. I am sure I had much more sleep deprived times in the hospital with Sydney and I guess I am just out of practice. Regardless, I have reached the limit on my ability to function - at least rationally. I had an incredible time. It was a jam packed adventure but I am anxious to get home and be with my family. Lynley has grounded me from travel any time soon and that suits me just fine. I am simply not made out for this jet set life. The only problem with this plan is that I will be heading out of town in just three short weeks for a CNCF board meeting. Quite frankly, if I wanted to (which I don't and I will not), there are places I could be every week for the rest of this year. As important as I know many of these trips are, I don't want to be away from my family. I miss my wife, my kids, and my normal average chaos around the house. Life is hard when you don't have a wife around to tell you what to do. That life is sleep deprived enough without all of this jet setting.

So, why did I make this trip. Well, it was important. I had to get up to speed on many of the issues on this project of humanizing the 3F8 antibody and I had to do it quickly. Honestly, I came into this a bit skeptical but, after hours of meeting and studying, I am pretty firmly on board with the idea. Research has been kind of funny the more that I have gotten involved and learned about the process. I have always fallen in love with whomever I talked with last but have learned that there is always more to the story. In this case, it is a subject that I know a fair amount about - antibodies. Given this experience, I went in with a pretty clear picture of what to ask. I can already envision and understand both sides of the coin and can make most of the arguments for myself. I know I still received a fairly biased point of view from Sloan but since I understand both sides I am able to strip away the bias and make a decision for myself. I think this is one reason why some families at Sloan are skeptical of me. I don't just believe in Sloan or the antibody itself. I also believe in the COG, the NANT, and a myriad of investigators from all over the world. Kids survive with all kinds of therapies from all kinds of institutions, being cared for by all kinds of different researchers. I agree that some places are better than others but there is no absolute answer and all of the "good" science does not happen at a single institution. With that being said, I can tell you that I am firmly behind this vision at Sloan and I think it is an important endeavor. I believe it will be one of several things that will impact our kids lives (kids of the NB world) and, for that reason, it is something I am willing to commit myself to supporting. However, it will not be the only great project that I will support and see through fruition this year. There are other great things happening that are likely to have as important of an impact.

So, why is this important? What in the H - E double hockey sticks am I talking about. Why I do I think humanizing this antibody is important? Don't we already have one? Why do we need it? As I have said before, the 3F8 is a murine (mostly mouse, about 75%) antibody. Because of this it has some theoretical advantages but the point is that it is a relatively old antibody with 20 years of experience. We know that 3F8 effectively kills neuroblastoma cells in kids and we also have a pretty good indication that it does it pretty effectively. The belief at Sloan is that it does it better than any of the other antibodies because it stays attached to the neuroblastoma cell for longer than the other antibodies. This is called the "come off" rate. You may remember me saying that that the humanized and chimeric antibodies live longer in kids than the 3F8. In other words, when kids are being injected with antibodies they stay alive and active within the kids bodies longer than 3F8 does. You might think this would be better. Ordinarily it would be but, the issue is more complex. It also depends on the stickiness of the antibody to the NB cell. Although the 3F8 may not live as long in the human body as the other antibodies, Sloan believes that it stays attached to the NB cell for much longer. This "stickiness" to the NB cell is what allows the immune system, those killer cells, to organize and kill the neuroblastoma cell. Basically, it stays attached to the NB cell long enough to kill it. Is this data published? No, of course I asked. But this is Sloan's reasoning for why they like their antibody better.

Given these "facts" why wouldn't everybody use 3F8 and keep taking the antibody indefinitely? Well, the 3F8 also has some problems. It is mostly mouse, remember, and the problem is that our human bodies become "allergic" to it more quickly and then our bodies develop our own antibody to mount a defense against it. Our bodies eventually start to kill the 3F8 faster and faster until it is virtually useless. This is the HAMA (Human Anti Mouse Antibody) response that I have talked about so often. So, even though a child could be benefiting from the treatment they can no longer have the antibody because it will cease doing any good. It will be killed before it can do its job on the NB cell. We had an effective treatment but we can no longer use it because it is too, well, mousy. This begs the question. How do we prevent this HAMA?

Well, first off they do it initially by taking advantage of the suppressed immune systems of these kiddos. These are the suppressed immune systems that we have achieved through the massive amounts of chemo they have endured during induction and sometimes transplant. So, yes, massive amounts of chemo will do it. However, that isn't a really great idea for these kids to give them more massive amounts of chemo once they have HAMA'd. That would come with significant risks and toxicities. What else can we do? And, this is where humanizing the antibody comes in. We make it more and more human so the body won't be as likely to develop a HAMA. We engineer the antibody so that the body will like it more. We replace parts of it with human parts while trying to leave the parts that make it so sticky. This is the process of humanizing the antibody. This has several advantages. Now we can potentially give the antibody to kids who would have HAMA'd early on. I have often said that it is my belief that we need long term continuous exposure to the antibody to work best. Humanizing the antibody will ensure that kids can receive enough exposure to the antibody without developing an antibody response such as the HAMA. Another benefit of humanizing the antibody is for kids who are not significantly immunosuppressed but heavily pretreated. They no longer require these high dose preparatory regimens of chemo to prepare them for antibody therapy. This goes beyond just preparation to prevent a HAMA. Ultimately it helps reduce the toxicity of treatment because children no longer need as much chemo to continue fighting this disease. They have more energy to fight. Kids could be treated for years without any chemotherapy. This will help the children that have relapsed maintain disease control for longer time periods. Their bodies will not wear out as quickly. Sloan states (and I know of examples) that they are maintaining disease control for longer and longer and patients are now surviving up to 10 years after relapse. This means time, which we can use to search for cures for these kids. In my opinion, no, this antibody is not the cure for cancer. But, it is a key player in buying time until the silver bullet can be found. Thankfully there are many promising therapies on the horizon we just need more time.

But aside from the reasons mentioned above there are many other benefits to humanizing this antibody. Much of which can't be readily seen by an amateur antibody lover such as myself can still be explained. And, I did get a glimpse into some of the possibilities. For instance, by genetically engineering this antibody from the ground up we now have the opportunity to muck with other aspects of the antibody. For instance, We can add elements to make it live longer. We can even make the other side of the antibody sexier. In this way, it will be more attractive to all of those big manly killer cells that we want be attracted to kill the NB cell. Humanizing it also makes it easier for us to "grow up" the antibody in hamster choke(?) cells. This means we can grow the antibody in larger volumes. This helps deal with some of the current drug supply issues. See, there are many good reasons for this antibody and it isn't just what we see on the surface. This is the body of theoretical, anecdotal, and belief in what Dr. Cheung is telling the truth that makes me believe in this project. I have to put my finger on what I know and makes sense and make a decision. In this world, you have to pick and choose who you are going to believe in and I can say that Dr. Cheung is one (of several) of the researchers that I believe in.

I have a rule for that. We share purpose!

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