Dr. Stanley Lewis Q & A

Dr. Stanley Lewis is the Vice President and Chief Medical Officer for TaiMed Biologics, Inc., managing the company’s clinical development pipeline, which primarily focuses on infectious disease. Before joining TaiMed, Dr. Lewis served as a Medical Director at Genentech Inc., assisting in the out-licensing of Ibalizumab, a first-in-class monoclonal antibody viral entry inhibitor for the treatment of HIV/AIDS.

Prior to Genentech, Dr. Lewis led the development of Ibalizumab for Tanox, Inc. through Phase 2a clinical trials.  Before focusing his efforts on drug development, Dr. Lewis was Assistant Professor of Medicine in the Department of Internal Medicine at the University of Texas (UT) Medical School in Houston. In addition to teaching students and residents, he concentrated his clinical work on treatment of people infected with HIV/AIDS while becoming an HIV Specialist of the American Academy of HIV Medicine. Dr. Lewis has served as principal investigator or co-investigator on numerous clinical trials (Phase 1-4) and has authored numerous publications related to HIV drug therapies and patient care. He was named a Trail Blazer in Medicine by the Brentwood Community Foundation.

Along with his primary responsibilities in drug development, Dr. Lewis continues to volunteer his clinical services at the St. Hope Foundation, a community-based HIV/AIDS service organization based in Houston, TX.

In the early days of July, 2010, the journal Science announced in two papers that researchers had discovered three previously unknown antibodies (adding to two others discovered a year prior) that could potentially lead to some very exciting advancements in HIV/AIDS treatments, vaccines, and possibly even an eventual cure.

SafePositive sat down with Dr. Stanley Lewis, a trailblazer in the use of antibodies in clinical HIV/AIDS research, to discuss how these scientific findings might translate into products to prevent or treat HIV disease.

SP: Dr. Lewis, could you give us a little background on the role of antibodies in HIV/AIDS treatment and what finding these antibodies means for the future of HIV/AIDS?

SL: Antibodies have yet to play a significant role in HIV treatment. The search for broadly neutralizing antibodies has been frustrating because HIV is such a diverse and adaptable pathogen and antibodies are very specific by nature. For almost everyone infected with HIV, the virus maintains the upper hand because it is a moving target. While antibodies and other elements of the immune system are activated to combat the infection, HIV eludes these defenses by it propensity to replicate rapidly and mutate.

SP: How does this sort of treatment differ from what’s currently available for people with the virus?

SL: As therapeutic agents antibodies, unlike small molecules (chemicals), are very specific. This specificity reduces the likelihood of off-target effects (i.e. side effects). This has been demonstrated in several areas where there are approved antibody treatments including cancer, asthma, autoimmune disorders, and infectious diseases. Antibodies are a key component of the immune response to infections. If present and neutralizing they can confer immunity.

SP: How would an antibody theoretically be able to cure the virus?

SL: We are not ready to translate the scientific findings into a cure just yet. However, the traditional means by which antibodies can effectively cure disease vary. For instance, a vaccine (antigen) can be administered that mimics infection in such a way that the body produces an antibody response neutralizing an actual infection if the host is exposed. 
Secondly, a therapeutic antibody can be manufactured that has specificity for a target so that once the antibody is attached, other elements of the immune system can clear the target from the body. Yet another way antibodies can be used to cure infections is to administer an antibody that attaches to a host target. By attaching to that target, the antibody prevents the disease from propagating. There are a number of variations to these approaches and some elements of the cellular immune system will need to be recruited for a ‘cure’, but I think finding these antibodies are a major step toward the cure. We now have a much better idea of what key antibodies looks like.

SP: Are there different risks and benefits between what’s being used now and the potential new class of treatments?

SL: Toxicity is always an issue with small molecule (chemotherapy) treatments. This is also true for the currently approved medications for treatment of HIV. Whether it’s issues created by absorption, metabolism or clearance, small molecules often have a large number of off-target (side effects) that can cause problems for patients and ultimately limit the usefulness of these agents. Antibodies have the potential to be extremely safe and tolerable. This profile is attributed to their specificity for their target. On the downside, antibodies are proteins and cannot currently be taken orally.  Subcutaneous or intravenous administration is required. Fortunately, these administrations are typically infreqent.

SP: Could you talk a little about ibalizumab and how the latest news coming out of the journal Science regarding antibodies impacts TaiMed’s plans for development?

SL: The Science article refers to host-produced (human) antibodies that target the virus. These antibodies are of particular interest because they are broadly neutralizing. Ibalizumab is also broadly neutralizing, but it is a humanized antibody that targets a host cell receptor.
Essentially, Ibalizumab uses antibody specificity to attach to human CD4+ T-cell receptors. The attachment does not appear to harm the T-cell, but it does prevent HIV from entering the cell, a key step in the virus life cycle. This blockade prevents the virus from accessing host cell machinery needed for viral replication. The Science article findings will not have direct impact on Ibalizumab development, but it does boost our confidence in our efforts to develop an antibody for treatment and potentially for prevention of HIV infection.

SP: To clarify and to possibly put this into laymen’s terms — when you say “truncates the virus’s life cycle” do you think that the antibody could ideally be used once the person is in the early stages of infection with HIV or as preventative for people involved in high risk behaviors?

SL: Both. Ibalizumab is a viral entry inhibitor. Preventing virus entry into target CD4 cells has been shown to reduce viral replication and improve the immune system.  Thus, Ibalizumab could potentially be a useful treatment for people infected with HIV. However, viral entry is an early step in the infection process. We believe that blocking entry might also be a useful approach to preventing infection in HIV negative people.

SP: As a clinician researcher, what advice would you give on how to properly temper the hype surrounding this potentially exciting news while balancing some of the negativity coming from naysayers?

SL: It’s difficult because this news is really exciting. Of course, this is also HIV and we should maintain a healthy respect for this virus’ ability to circumvent our efforts to eliminate it. The naysayer camp is probably comprised of those that don’t believe we can get the upper hand because previous efforts have been so disappointing. But this finding is different. This time we have started with a successful phenotype (people that control the virus) and worked backwards. We asked them to show us what it is that their immune system knows that the rest of us don’t know about controlling HIV.  And by looking in the right place, we may have found what we’ve been looking for. Translating these findings into a therapeutic (vaccine or medication), is a long way off. But like Churchill once said, “Alas, we’re reached the end of the beginning”.

SP: You mentioned that in the past researchers had looked for neutralizing antibodies from people who produced significant antibodies but were not able to control the virus. What did you learn from that approach and how does this compare to previous approaches?

SL: Previous approaches focused on screening the antibodies of people that produced a large number of anti-HIV antibodies when infected. I think we learned something obvious — that people who produce a lot of antibodies but don’t control viral replication don’t have antibodies that can control viral replication.
People that control their infection (known as ‘controllers’ or long-term, non-progressors) don’t necessarily produce a lot of antibodies post-exposure/infection. The approach used by the group that published the Science article focused on screening people that control their infection. Not only do these ‘controllers’ have fewer antibodies to screen (a smaller pool), we suspect that within that small pool there must be neutralizing antibodies (hence the phenotype). I’m far more pleased by the findings than I am surprised by them. Sometimes life is a game of ‘Paper, Rock, Scissors’.  HIV has had paper for over two decades while we’ve been holding rocks but perhaps we’ve finally found some scissors.