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  ICAAC 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
Chicago, Illinois, December 16-19
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Entry Inhibitors
Written by: Michael Norton, PA, Boriken Family Health Clinic
  John Moore delivered one of three keynote addresses the opening night of the 41st ICAAC. His topic and expertise is entry inhibitors and he reviewed the field. This report summarizes his presentation.
It is expected that entry inhibitors will have activity against all subtypes of HIV.
An update on a few of the entry inhibitors under development.
T20 is the entry inhibitor that is the farthest along in development. Multiple NATAP reports have been written describing its activity. T20 works by blocking GP41, an essential viral protein utilized by HIV for entry into a host cell (CD4s). The compound is currently under development by Trimeris/Roche, it is currently available to some patients through a limited expanded access program. It is expected that its makers will file NDA's (new drug applications) to the FDA for approval sometime in 2002. T20 is synergistic with RTI's and PI's - the currently available HIV antiviral drugs.
Challenges that exists for T20 are:
- The manufacturer has had difficulty producing adequate quantities of the drug, but this is now felt to be a solved problem.
- Patients must self inject once or twice daily due to a short half-life of the compound. A subcutaneous delivery system is currently under investigation.
Unfortunately, resistance to T20 does develop. The resistance develops due to changes by the virus in its envelope protein (GP41).
T1249 is the second generation of T20. Look for a full NATAP report from this 41st ICAAC describing its characteristics and progress in development.
PRO-542 is an entry inhibitor composed of CD4's (CD4 receptors) attached to an IgG molecule and is an improved version of the old soluble CD4 concept. This makes it a relatively large molecule and large molecules are not bioavailable if taken orally, thus it too will be an injectable. Its half-life is measured in days, which means that injections will be less frequent then daily. PRO-542 is made by Progenics.
Anti CD4 monoclonal antibody. Dr. Moore mentioned that an anti-CD4 monoclonal antibody from Tanox Inc. was going into a phase I human safety trial in 2002. An anti-CD4 antibody would conceivably inhibit HIV entry into a CD4+ T-cell because this antibody would be sitting on the CD4 receptor blocking HIV's ability to use it. It is generally agreed that CD4 receptors play a vital role in the immune system. Therefore potential problems may arise by blocking a significant number of CD4 receptors. Still Dr. Moore stated that in an animal model this monoclonal antibody did not appear to be immunosuppressive.
AMD 3100 is an injectable CXCR4 inhibitor from AnorMED. Recall that in addition to CD4 HIV requires a second receptor to gain entry into CD4+ T lymphocytes. That second receptor can either be CXCR4 or CCR5. Most HIV virus use CCR5 in addition to the CD4 receptor to enter the host cell. However CXCR4 remains important due to the fact that CXCR4 utilizing virus appear to be more virulent. A virus that infects T-cells via the CXCR4 route more rapidly leads to a decline in T-cells and also causes syncytia (a phenomena where HIV can cause giant infected masses of cells to stick together like Velcro). Unfortunately AMD 3100 has been abandoned due to cardiac arrhythmias. Even without the arrhythmia problem, AMD 3100 did not show enough antiviral efficacy. It also caused a significant increase in WBC's (white blood cells) within hours of exposure to the compound. It is thought that this was possibly due to the receptor CXCR4 being utilized by WBC's to hold onto tissue binding sites. Thus once the CXCR4 receptors were blocked by this drug, the WBC's were unable to adhere to tissues and would thus give rise to the increase seen in WBC's on the subsequent blood draw.
PRO 140 is a monoclonal antibody against CCR5, from Progenics. Recall that CCR5 is the co-receptor, along with CD4, utilized most often by HIV for entry into a T-lymphocyte. CCR5 virus are non-syncytial viruses, although they are still cytopathic. 95% of sexual transmission of HIV is thought to be through the CCR5 co-receptor pathway. Thus finding effective and safe CCR5 blockers could prove monumental. Fortunately CCR5 does not appear to be essential for human health. A number of individuals are genetically deficient of the CCR5 receptor on their T-cells. It is assumed that these folks have difficulty acquiring HIV infection and if they do it is thought that they progress to AIDS at a much slower rate.
TAK 779 is a CCR5 inhibitor that, according to Dr. Moore, "isn't going anywhere." It was tested in the laboratory and found to be active against HIV, but it had poor pharmacology properties when tested in clinical trials and so was abandoned. No details provided.
SCH-C is an important and exciting CCR5 inhibitor from Schering-Plough. It is the first entry inhibitor that is a small enough molecule to be orally bioavailable. Pre-clinical work is complete on this compound. It was shown to have antiviral efficacy in a SCID/hu mouse model. It did have some cardiac (QT complex) irregularities that held up it development for a while, however at this time it is going forward in trials in HIV-infected people. Information on its antiviral efficacy in humans has not yet been released by Schering-Plough, and is eagerly awaited.
SCH-D is also a CCR5 inhibitor being developed by Schering-Plough. It is, according to early reports, more potent then SCH-C in the laboratory.
Possible Problems:
Will using CCR5 blockers drive HIV to utilize CXCR4 for entry into T-lymphocytes creating a more rapid decline in T-cells and a more deadly natural course in HIV infection? According to Dr. Moore, early studies in the laboratory suggest that this is not the major pathway of escape from molecules like SCH-C, but this issue will need to be carefully studied in clinical trials.
Smooth muscle cardiac cells contain CCR5 receptors? Will taking a CCR5 blocker lead to heart problems?
Possible Benefits:
Entry inhibitors are known to synergize due to the fact that they have different mechanisms of action. Thus utilizing T20 or T1249 along with a CCR5 inhibitor will hopefully provide powerful HIV suppression and perhaps even replace the current HAART drugs. If so, the people who made the various entry inhibitors will deserve the credit, and not just the people who tested them - unlike what happened with existing HAART.
One of the most promising areas of research is the possibility of developing an entry inhibitor (or combinations) that could be put into a topical microbicide. If this were successful, it could potentially decrease sexual transmission of HIV and have implications worldwide for the control of HIV epidemic. To be continued...