Monoclonal antibodies provide new hope for easier dosing
by Jeannie Wraight
With multi-drug, once-a-day therapies now available for use, the push for additional easier to manage and tolerate HIV drug regimens has never been greater. Whereas Atripla and Stribild offer simple dosing, ARV-related toxicities and side effects continue to make drug adherence difficult. Of the several new classes of drugs in the HIV drug development pipeline, monoclonal antibodies (mAbs), may offer a great possibility for a potent, less frequent dosing option with relatively few side effects.
Monoclonal antibody-based therapies are already used in many different diseases such as lymphomas, leukemias, transplant rejection, autoimmune disorders, rheumatoid arthritis, psoriatic arthritis, and Crohn’s disease.
Generally speaking there are two types of monoclonal antibodies being researched for use in HIV-positive individuals: those that target cell surface receptors and those that target virus-activated host factors. These and other mAbs are administered subcutaneously or intravenously and may be able to be dosed bi-monthly or once a month as they are substantially more potent than current HIV antivirals.
TSG101, Nedd4, and ROBO1 are examples of host proteins that are located on the membranes of cells once they have been infected with viruses such as HIV and influenza. These host proteins have been found to be essential to the life cycle of HIV in the cell. A better-known host cell protein is CCR5, a co-receptor found on cells that are both healthy, non-infected cells as well as those infected with HIV. Some people have a genetic mutation that deletes CCR5 (delta 32), making them resistant to HIV infection.
TSG101 does not change when the virus itself changes, such as when it mutates to overcome the effectiveness of certain drugs. This makes it the perfect target for an HIV drug as resistance to a therapeutic may not occur as it can with other antiretrovirals. FGI-101 (made by Functional Genetics) is a monoclonal antibody made to target TSG101 on cells infected with HIV. When FGI-101 binds to TGS101, the immune system is triggered and kills the infected cells.
A combination of available ARVs that targets stages of the HIV lifecycle such as reverse transcriptase (NTRIs) or protease inhibitors (PIs), along with monoclonal antibodies, could provide the body with a stronger punch to rid itself of HIV in active cells. By targeting virus-activated host proteins, FGI-101, or similar monoclonal antibodies, could reduce and or eliminate the concern for drug resistance. By specifically attacking only the host factors that are activated by the virus, healthy cells and tissues are not damaged by the monoclonal antibody.
This approach is being investigated as a broad spectrum therapeutic which could be used for several diseases in addition to HIV including CMV, herpes simplex, influenza, and Ebola.
Within HIV, ongoing research of monoclonal antibodies is being conducted on all types of HIV-1 and HIV-2 strains as well as viruses already resistant to available antivirals.
Bavituximab (developed by Peregrine) is being studied for hepatitis C (HCV) and HIV/HCV co-infection. Bavituximab targets and binds to phosphatidylserine (PS), which is present on the membrane of cells infected with HIV, HCV, herpes virus, influenza, and several other viruses.
Mounting evidence shows PS to be an important part of the HIV infection process, particularly in regards to macrophage cells. Dr. Barton Haynes, MD, director of the Duke Human Vaccine Institute, is leading the way in clinical and vitro research to determine the precise significance of phosphatidylserine in HIV.
In discussing a Duke University study of PS, Dr. Haynes commented in an E! Science News article, “These results indicate that targeting a host cell lipid such as PS as an anti-viral strategy is a promising concept of relevance to new therapeutic and possibly prophylactic innovations for HIV.”
In a twenty-seven-patient, eight-week, Phase Ib safety study of HIV/HCV co-infected individuals, Bavituximab was found to be safe with mild to moderate adverse events and produced two serious drug-related adverse events. A further study of Bavituximab in people with HCV is currently ongoing.
CCR5 mAbs are monoclonal antibodies that target the CCR5 receptor before HIV is able to infect a CD4 cell. They have demonstrated broad and potent antiviral activity in vitro and have been shown in clinical trials to have prolonged activity with a single dose. Studies on long-term use of CCR5 mAbs would determine if these therapies are safe and effective for continual use.
HGS004 (developed by Quest Clinical Research) is a fully human monoclonal antibody that targets CCR5. In a single-blind, randomized, placebo-controlled study of sixty-three patients with CCR5-tropic HIV, HGS004 was found to be safe, well tolerated, and effective. Study participants were given a single intravenous dose of HGS004 at one of five doses. No toxicities were observed and a tenfold reduction in viral load was seen in fifty-four percent of the study participants.
TMB-355 (Ibalizumab) (made by TaiMed Biologics) is a CCR5 monoclonal antibody in Phase II clinical study. In a 113-person study of Ibalizumab, viral load decreases were observed at two different doses of the drug in addition to ARVs. At week twenty-four, thirty-six percent of participants had undetectable viral loads, forty-eight percent under 200 copies, and fifty-two percent under 400 copies.
Although still early in clinical research, monoclonal antibodies appear to offer a new potential avenue of combating HIV. Research should be continued and supported by the National Institute of Allergy and Infection Diseases (NIAID) utilizing the AIDS Clinical Trials Groups (ACTGs) and the Military HIV Research Program (MHRP) to ensure clinical study in vast international populations of people with various HIV strains.
Jeannie Wraight has been an AIDS treatment activist and HIV writer for over fifteen years. She lives in New York City.