-------------an interview with Dr. Eric Rosenberg
by Search For A Cure, October 2011
For over twenty years, Search For A Cure has published articles about HIV in some 400 community newspapers, and maintained a website (www.searchforacure.org).
Our mission has been to ensure that whenever we discover some potentially useful therapy for HIV that the therapy is studied well, and when available, is priced and distributed in a manner that allows everyone with HIV to access it.
This includes therapies useful to inhibit HIV transmission, technically a 'public health' issue, exemplified by our present effort in Massachusetts to pass a new law called H2908 to get Pre and Post exposure prophylaxis and rapid HIV assays targeted to and available to those most likely to benefit from them as well as to remove legal and public policy obstacles to the use of ‘high impact prevention’.
Several years ago Search For A Cure ran across a new therapy for HIV called ‘Cytolin’, which is a ‘monoclonal antibody’, and researched how progress on its development was going.
We discovered that some 188 people had used this antibody prior to 1996’s advent of full antiviral cocktails in a compassionate use protocol with encouraging results.
Prompted by these initial findings, we did a background check on Cytolin, interviewing major scientists like Joseph Sodroski of the Dana Farber Cancer Institute, Michel J. Tremblay from the Centre de Recherché en Infectiologie, Universitaire de Quebec; Norman L. Letvin, M.D. Beth Israel Deaconess Medical Center; Edmund Tramont, M.D., Director Special Projects, NIH; and Donald Northfelt, M.D., Mayo Clinic. Each of these people indicated with varying degrees of support that this antibody might be of some use in HIV infection.
Recently, a study to determine the actual mechanism of action of Cytolin was initiated at Massachusetts General Hospital in the laboratory of Dr. Eric Rosenberg. The purpose of this story is to update you on the recent progress made towards bringing Cytolin back to the clinic.
Monoclonal Antibodies and their use as therapies for HIV
Let's start with a little background about monoclonal antibodies. This type of therapy has become increasingly valuable for many kinds of diseases. There are 30 such antibodies approved by the FDA, among them are antibody therapies for breast cancer, leukemia, Crohn's disease, psoriasis, melanoma, allergy related asthma and several autoimmune disorders including rheumatoid arthritis. You can get a complete list of those currrently approved using the link below:
Monoclonal antibodies are also being studied as a therapy for HIV. Ibalizumab (all antibody therapies end in 'mab' for 'monoclonal antibody') is an entry inhibitor that binds to CD4. It is designed to stop HIV from getting into a cell. Recently, the results of a study testing Ibalizumab in 113 highly treatment experience people whose medicines were failing them was reported. You can find out about it at:
Because Ibalizumab is not a drug it has an excellent safety profile. In fact, according to David Ho, one of the co-developers of Ibalizumab;
“Such antibodies are not only well tolerated and have an excellent safety record, but are also administered infrequently because of their long half-life as compared to small molecules. We believe this could be the next generation of medications to treat HIV.”
However, because it tries to interfere the binding of gp120 from the virus to the cell there is evidence that subjects can develop resistance to it. We mention this observation to explain why Search For A Cure is so optimistic about the potential for Cytolin. What makes Cytolin unique is its target. Unlike Ibulizamab, which sticks to CD4 to try to block the gp120 protein made by the virus, Cytolin blocks a cellular antigen called LFA-1 that is stolen by the virus and used for infectivity. Because the virus does not have the gene for LFA-1 it cannot mutate around the therapy. This makes it unlikely HIV will get resistant to Cytolin.
Historically, there has been a lot of evidence that this type of therapy could help treat HIV. We included the references for some of these reports below (see footnotes 1-5.) As with drug cocktails, people have also examined the effect of combining different types of entry inhibitors, including those that inhibit LFA-1. A revealing quote from the last article listed below supports this approach:
“All together our data suggest that LFA-1 antagonists represent promising antiviral agents. Anti-adhesion therapy could be considered as a complementary strategy targeting cellular functions essential for HIV-1 spreading and against which the combined therapy currently used displays a limited efficacy.”
Search For A Cure approaches Dr. Eric Rosenberg
Because we felt anything that might help treat HIV needs to be carefully studied and because of the support from scientists we respected, we brought our background materials to Dr. Eric Rosenberg, a professor at Harvard Medical School, who has spent much of his life studying HIV infection and treating patients with this disease.
Dr. Rosenberg is one of our most respected, seasoned and innovative scientists who has spent years working on treatment of people in the early stage of their HIV infection.
He agreed to study this antibody in his laboratory to determine its mechanism of action.
Below is the interview we conducted with Dr. Rosenberg at his office in the Massachusetts General Hospital. We are publishing it in order to provide an update, as we try to do diligently, for all of those activists and friends who are following the development of new kinds of therapies.
Interview with Dr. Rosenberg
Question from Search: As people read through the Q&A one thing they will have in their head is why did you decide to do this type of thing with your life? What was the motivation for working both with respect to HIV but also doing research in medicine?
Answer from Dr. Rosenberg: Two fold. First when I was in medical school and in the early part of my training it was the mid 1980’s and HIV was really ripping out of control in the place that I was training. I trained in NYC and 30% of our hospital beds were occupied by HIV infected individuals with really serious life threatening opportunistic infections and little promise for effective antiretroviral therapy. That is the background that I come to this through, because it was really hard to see people my own age who were dying of HIV and AIDS. With that being said I never really did think that I would go into science. I was focusing my energies on being a clinician until I trained in infectious disease and had a laboratory experience doing HIV immunology and that really turned me on to trying to find a way to augment host immune responses so that the body fights back better against HIV.
Search: So host immune augmentation, is that your preferred area of research?
Dr. Rosenberg: It is one area of research. I am most interested in understanding immunosuppression and how under averse circumstances the body fights off infection.
Search: How many years have you been dealing with HIV and immune augmentation?
Dr. Rosenberg: Over twenty years.
Search: We know you have been working on treating people immediately after infection- how is that work going?
Dr. Rosenberg: For many years I have been interested in seeing how to help the immune system manage HIV infection more successfully, preferably without the need for lifelong use of medicines. We have been trying to see if intervening with medicines and vaccines in very early (acute) HIV infection. to seeif early treatment can preserve HIV-specific immune responses. There is some evidence this could be possible.
Search: So Cytolin, it may be useful for HIV and it is a monoclonal antibody. What is a monoclonal antibody?
Dr. Rosenberg: First we should look at what is an antibody. An antibody is a molecule made by B cells, a type of white blood cell in the body and an antibody has a very high specificity for a given molecule. Antibodies are one reaction the immune system has to discovering a foreign body whether it’s somebody else’s skin in a transplant or a germ that doesn’t really belong in the body. Antibodies are things the body makes that stick to these foreign bodies and often they help the body get rid of them in different ways.
Search: What category of medicine do monoclonal antibodies fall under?
Dr. Rosenberg: They are unique: they are antibodies that are all the same made by identical immune cells cloned from an original. This is good because you can count on them to behave in more or less predictable ways. They are, like vaccines, an immune based therapeutic when used as medicine.
Search: Why are these antibodies called ‘mono’ instead of just ‘an antibody’?
Dr. Rosenberg: Because each antibody has a given specificity, similar to how every key fits into a very specific type of a lock in a door. Antibodies are the same way, your body makes billions of different types of antibodies and each antibody recognizes a very specific type of target. The body makes lots of different kinds of antibodies; a monoclonal antibody is just basically an antibody with one clonal type. So it is an antibody produced in great quantity that only recognizes a very specific thing.
Search: So it is like Xeroxing one of them?
Dr. Rosenberg: Exactly, you are Xeroxing one.
Search: Sure. Now, I have been noticing when I read through things for the first time in the 20 years I have been looking at it that all of a sudden there are lots of antibodies available for all sorts of things, so what other kinds of disease treatments or medicines are using antibodies now as treatment as opposed to say 15 years ago?
Dr. Rosenberg: There is a relatively new field of therapeutics that we refer to as ‘biologics’ and biologics are medicines or products that are biologically active and typically may be made by the body. So the greatest use in 2011 for antibody based biological therapy is in the autoimmune diseases, because you could use a monoclonal antibody to bind to a certain type of cell that may be out of control and causing autoimmune diseases.
Search: Is that like arthritis?
Dr. Rosenberg: Yes, and once the antibody binds to a specific target then that target and cell may actually be eliminated from the body, and it is one way of using antibodies as a targeted form of therapy.
Search: What is the work you are doing with Cytolin?
Dr. Rosenberg: Let’s start with what were some of the early observations in people in which Cytolin was originally used. Some people were given this antibody on a compassionate use basis that resulted in the interesting observation that in some individuals, viral loads dropped and CD4 counts went up. None of these were randomized controlled trials, but we are left with the observation, at least to the physicians administering the medicine, that this monoclonal antibody when given to HIV infected individuals who are out of standard therapeutic options seemed have some benefit. Unfortunately, these stories were mostly anecdotal and therefore it is impossible to know for sure if Cytolin does anything beneficial.. So that was really the basis for wanting to understand in much greater detail if this is a legitimate observation because if so it could be a legitimate therapy, and also what is the mechanism of action? How do you explain what this antibody is doing in the body that would result in HIV viral load dropping and CD4 counts rising?
Search: Well to that affect, you spent a little bit of time looking at this antibody in the lab already and you are continuing to work with it so what might you be at liberty to share so far as to what is of interest to you and what you are learning?
Dr. Rosenberg: I think that we are very early in our studies and so we are really not at liberty to say much because we need to do more work, but what I can say is that we have found one or two interesting observations that, if they pan out, may help explain the affect that this antibody is having or how the antibody is actually working
Search: If you look just at the field of HIV right now there are a large number of approved antiretrovirals in different classes already. In what way would a biologic like Cytolin, be of use?
Dr. Rosenberg: So in other words when you have 25 or more medicines that are already approved for use in treating HIV how would this, if it was effective, where could this play in treatment strategies?
Dr. Rosenberg: We are not going to know for sure until we understand this antibody better and it goes through clinical trials to see how effective it may be in humans, but I could imagine or I could hypothesize that there are several situations where it may be useful. One situation is relatively early in the course of infection when prior to somebody meeting the traditional criteria for starting antiviral therapy. Perhaps if you gave a monoclonal antibody like this to somebody before they meet the need for starting antiviral therapy, if you can get a drop in viral load and a rise in CD4 count you may prolong the time in which they can actually stay off of standard HIV therapy. So one theoretical use would be to give it early in disease to buy somebody more time off of traditional HIV medicines.
The other potential or theoretical use would be at the other end of the spectrum in those individuals who had run out of other therapy options. Somebody who has got highly drug resistant virus and is not able to bring the viral load down or the CD4 count up using traditional antiretroviral medicines, perhaps giving an antibody like this may buy somebody time or may help to control infection for a longer period of time because they don’t have other drugs that are necessarily effective. That situation would be known as a salvage therapy, where you have run out of your standard options and you are using this to achieve a similar effect.
Search: Is there any a priori reason to think or believe that using an antibody of this type if it were to work, as an additional component to a cocktail of some kind, would be beneficial?
Dr. Rosenberg: I could imagine situations where using an antibody in the presence of antiviral drugs could be synergistic. That is there could be an added beneficial effect. But it really all will come down to how this antibody works, and so in order to understand what the effect is going to be of the antibody we first need to determine how it works, and until we do that it is impossible to predict whether there would be any sort of additive or beneficial effect.
Search: Is it equally unknown whether or not the virus will grow resistant to Cytolin like it does to most of the drugs that I have read about and looked at over the years? Is there any reason a priori to think that the virus could get resistant to this antibody? Or is there anything about antibodies that makes them fundamentally different than the drugs that are being used to treat HIV right now?
Dr. Rosenberg: If the antibody is working by binding to a specific part of the virus, we know that there is a high likelihood that the virus may mutate and change and escape from the ability of the antibody to bind. However, there is a good chance that if this particular monoclonal antibody works, that it is working through a more indirect mechanism, where it is not actually binding to virus itself but it may be binding to a cell and telling the cell to do something that may have an antiviral effect.
Search: If that happened would that make it less likely that the virus could figure a way around that?
Search: Did studying this so far teach you anything new about HIV, as opposed to the antibody?
Dr. Rosenberg: It may, and I say it may because it really depends on the next phase of our studies if we could take some of our observations a little bit further not only will we gain insight into how this antibody is working but we may also be able to learn other different strategies that the body may employ to fight viruses.
Search: The antibody is being humanized. Can you explain a little bit for a lay audience what does that mean and why is it relevant? (Ed. The antibody has been successfully humanized recently)
Dr. Rosenberg: Antibodies are not something typically made in a laboratory, usually antibodies are grown from another living thing. The first generation was actually made from mice, so it is a murine or mouse based monoclonal antibody and the next generations of antibodies that are being developed are “humanized” to look and possibly behave more like an antibody antibody made by a human instead of a mouse. In the case of Cytolin, they are actually putting human sequences into the mouse cell, which is a way to humanize the murine version.
Search: We already know it has been used in people, but are there likely to be clinical trials with this?
Dr. Rosenberg: I would guess that when we figure out in a convincing way the mechanism of action of this antibody and if it seems, based on what we learn, plausible and likely that administering this antibody would have a beneficial effect then I would image that the next step in development would be to do studies in humans.
Search: For more information about future clinical trials with Cytolin visit www.CytoDyn.com
As more information becomes available with this and other important therapies on the horizon we will continue to post it on our site at www.searchforacure.org.
- Antibody to Adhesion Molecule LFA-1 Enhances Plasma Neutralization of Human Immunodeficiency Virus Type 1,Marisela et al The Leukocyte Immunochemistry Laboratory, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
- LFA-1 Is a Key Determinant for Preferential Infection of Memory CD4 T Cells by Human Immunodeficiency Virus Type 1 Melanie R. Tardif and Michel J. Tremblay* J. Virol Nov. 2005, p. 13714–13724 Vol. 79, No. 21
- Human hepatoma cells transmit surface bound HIV-1 to CD4+ T cells through an ICAM-1/LFA-1-dependent mechanism. Fromentin R, Tardif MR, Tremblay MJ. Virology. 2010 Mar 15;398(2):168-75. Epub 2009 Dec 24.
- Presence of host ICAM-1 in human immunodeficiency virus type 1 virions increases productive infection of CD4+ T lymphocytes by favoring cytosolic delivery of viral material. Tardif MR, Tremblay MJ J Virol. 2003 Nov;77(22):12299-309.
- LFA-1 antagonists as agents limiting HIV-1 infection/transmission and potentiating the effect of the fusion inhibitor T-20 Mélanie R. et al, Antimicrob. Agents Chemother. 2009