The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex

Article Abstract:

A new substance which may be useful in the treatment of AIDS (acquired immunodeficiency syndrome) and AIDS-related complex is a soluble form of the protein CD4, which is manufactured using genetic engineering techniques. CD4 is the receptor on T lymphocytes to which HIV binds so that it can enter and infect the cells. The theory behind the use of soluble CD4 is that the virus will bind to the freely circulating soluble CD4, which is injected into infected individuals in large quantities. It is hoped that all of the virus will bind to the soluble CD4 and there will be no virus left to bind to the CD4 which is present on the cell surface; in theory this should inhibit infection. A phase I trial using various doses of soluble CD4 was conducted with 42 patients who had AIDS or AIDS-related complex, to test the safety and the pharmacokinetics, or action, of the agent within the body. Doses of 1, 10, 30, 100, and 300 micrograms per kilogram of body weight were administered intravenously on a schedule that lasted for eight weeks. To determine the best method of giving the drug, another group of 12 patients received doses of 300 micrograms per kilogram of body weight, either intramuscularly (injected into the muscle) or subcutaneously (injected under the skin). It was determined that 51 percent of the protein reached the blood from an intramuscular injection versus 45 percent from a subcutaneous injection. No important clinical, immunological or hematological toxicity was seen in any of the patients. Fortunately the levels of CD4 cells remained the same, indicating that no undesirable immune response was mounted against the CD4 on T lymphocytes. However, no reduction in the levels of HIV proteins was seen; such a reduction is desirable because it would indicate a decrease in HIV infection. The blood levels of soluble CD4 that were reached were equivalent to those previously determined to be necessary to inhibit replication of the virus in the test tube. While this study showed that CD4 was tolerated well and was safe at the doses used, further studies are necessary to see if soluble CD4 will be effective in treating patients with HIV infection. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Soluble CD4: the first step

Article Abstract:

Although an enormous amount of information is known about HIV (human immunodeficiency virus), the virus which causes AIDS (acquired immunodeficiency syndrome), the techniques available to inhibit HIV from causing infection are still limited. A new agent which has potential use in the treatment of HIV infection is a soluble form of CD4, the receptor on T lymphocytes to which the virus binds, allowing it to enter the cell. The theory behind the use of soluble CD4 is that the virus will bind to the soluble CD4, which has been injected into the bloodstream of infected individuals in large quantities and circulates freely. It is hoped that all of the virus will bind to the soluble receptors and there will be no virus left to bind to the CD4 which is present on the surface of healthy cells. In this way, infection of body cells would be prevented. However, the practical application of this theory is complicated. The immune system might recognize the soluble CD4 as foreign, creating an immune response to it and to the T cells that naturally contain it. This could cause destruction of the T cells, which are necessary for an immune response against the virus, making the condition of the patient worse. An immune response to the soluble receptor could also cause suppression of the immune system, inhibiting a response against the virus. However, phase I trials to test soluble CD4 have been promising, showing that concentrations up to 30 milligrams a day do not adversely affect the immune system. Further study is necessary in many areas of the therapy including: the modification of CD4 so that it can be administered more effectively to maintain high blood levels; long-term toxicity; and addition of substances to CD4 to make it toxic to the virus. The most effective therapy against the development of AIDS would be one that inhibited the virus at different phases of its life cycle. The use of soluble CD4 could be an important part of that therapy. (Consumer Summary produced by Reliance Medical Information, Inc.)

Immune recognition, editorial

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Recombinant soluble CD4 therapy in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex: A phase I-II escalating dosage trial

Article Abstract:

A new drug which may be useful in the treatment of AIDS (acquired immunodeficiency syndrome) and AIDS-related complex is a soluble form of the protein CD4. CD4 is the receptor on T lymphocytes to which the human immunodeficiency virus (HIV) binds, allowing it to enter the cell. The theory behind the use of soluble CD4 is that the virus will bind to the freely circulating soluble CD4, which is injected into infected individuals in large quantities. It is hoped that all of the virus will bind to the soluble receptor and there will be no virus left to bind to the CD4 which is present on the T lymphocyte cell surface; this would prevent HIV from infecting these cells. A phase I-II escalating dosage trial was performed with 25 patients who had AIDS or advanced AIDS-related complex to test the safety and efficacy of the drug, soluble CD4. The patients were given up to 30 milligrams a day for 28 days; no significant toxic effects were seen. The blood levels of soluble CD4 that are believed necessary to inhibit replication of HIV (as determined by testing in the laboratory), were achieved by giving patients doses of either 9 or 30 milligrams a day, injected into the muscle. At the concentration of 30 milligrams a day but not at lower doses, levels of an HIV protein were shown to decrease, which constitutes preliminary evidence that soluble CD4 has antiviral activity in HIV-infected patients. Further studies will be necessary to evaluate the use of higher dosages for longer time periods, and the use of soluble CD4 in combination with other anti-viral agents. (Consumer Summary produced by Reliance Medical Information, Inc.)

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