FDA BASIC RESEARCH ON SOLUBLE CD4

FDA BASIC RESEARCH ON SOLUBLE CD4 has led to development of "full-length" CD4 molecules that may have longer activity than soluble CD4 under development by Genentech and Biogen, FDA Division of Cytokine Biology, Laboratory of Molecular Immunology Acting Director Michael Norcross, MD, told a June 27 FDA Science Writers Seminar. The full-length CD4 molecules were developed through the use of human CD4 and insect vectors. "A number of companies have made CD4 in a soluble form that can be given I.V. [intravenously] or I.M. [intramuscular], which would bind [with] the virus and block its penetration. I decided to take a slightly different route and express a full-length molecule that could be incorporated into liposomes as a drug carrier," Norcross explained. When attached to a liposome, the full-length CD4 may have a half-life "about triple the half-life" of soluble CD4, "which lasts between 15 and 30 minutes," he said. Norcross noted that full-length CD4 has an anchor that enables it to attach to a liposome, while soluble CD4 does not. The CD4 research is being conducted in the Center for Biologics Evaluation and Research's molecular immunology lab. The lab is also investigating how AIDS patients treated with CD4 are affected by antibodies to CD4 and the HIV envelope protein. In addition, the lab is coordinating with the National Cancer Institute's Radiation/Oncology Branch on development of a technique for targeting soluble CD4. Biogen is supplying the lab with soluble CD4 free of charge. Norcross explained the targeting technique: "We've taken soluble CD4, coupled it to a chelate, which is like a cave that will hold radionucleotides . . . then test it for cytotoxicity and binding on cells." He pointed out that there are advantages in using a radioactive compound versus a toxin coupled to CD4: "it minimizes the normal tissue damage that you would see with lots of other toxins" and "it has a very short half-life . . . between an hour and two hours -- which is more compatible with the half-life of soluble CD4." He added that the short half-life "would then avoid a prolonged radiation exposure." The most beneficial characteristic of the radiolabeled CD4 is "that it does not require internalization in order to be cytotoxic," Norcross said. The lab has been testing the affects of these conjugates labeled with bismuth 2-12. "There seems to be a small effect of decreasing the replication rate of cells that are infected," Norcross said, noting that the researchers are pursuing ways to improve the effectiveness of the conjugates, including increasing the amount of the radioactive compound. Discussing the lab's investigation into the effect of CD4 antibodies on patient response to CD4 treatment, Norcross said he "suspect[s] . . . that they may not block the binding between CD4 and gp 120, [and] therefore will not interfere with this new therapy and actually may potentiate the activity of the recombinant product." One study, he noted, demonstrated that with "low concentrations of CD4, the antibodies actually potentiate the binding of CD4 to the surface of the cell." In another study, the lab found that antibodies directed against the HIV envelope bind to the same site on the cell as the CD4 molecule. "What we find is that there are antibodies against envelope that would block the binding of CD4 and [that] most people infected with the virus contain these antibodies." Norcross expects the studies to be published soon in clinical journals.