Shot in the Dark

Blocking the "Bad" Interleukins: Anti-IL-4 and IL-13

Another IBT strategy involves blocking potentially harmful cytokines. A small biotech company called Regeneron is developing a product called IL-4/IL-13 Trap based on the idea that these cytokines inhibit virus-specific CD8 T-cell responses. Results from a phase I dose-ranging trial in HIV-negative volunteers were presented at the 2004 Retrovirus conference, showing that the construct was well tolerated with a long half-life of 13 days. Further studies in HIV-infected individuals are planned.

Glaxo Dusts Off Something for APCs

Tucaresol is a relatively obscure IBT candidate that has languished in GlaxoSmithKline's HIV drug portfolio since the early 1990s. The drug appears to enhance interactions between antigen-presenting cells and T cells and has been shown to boost cell-mediated immune responses both in mice and in humans. Preliminary data from a phase I trial in 17 HIV-infected individuals were presented at the 2004 Retrovirus conference, demonstrating increases in naive CD4 T-cell counts and the number of T cells containing TRECs (a potential marker for T cells recently produced by the thymus) in the group of participants receiving HAART treatment. Larger studies are now likely.

Two That Target Defective Cellular "Signaling"

Two experimental IBTs aim to influence T-cell function by interacting with signaling molecules on the T-cell surface. One such molecule is CTLA-4, which is upregulated on T cells in HIV infection and associated with the induction of T-cell unresponsiveness or anergy. In June of 2003, the biotech company Medarex launched a phase I trial of an anti-CTLA-4 antibody dubbed MDX-010 in heavily treatment experienced HIV-infected individuals that are failing HAART, with the aim of blocking the suppressive activity of CTLA-4 and thus improving HIV-specific immunity. Results from this study have not yet been presented. Another molecule that is a target for IBTs is CD40. Signaling via CD40 is triggered by CD40 ligand (CD40L) and can potentially enhance the function of otherwise lethargic virus-specific CD8 T cells. The rights to CD40L were held by Immunex, a company that was recently bought by Amgen. The current developmental status of CD40L is unclear as Amgen did not return calls prior to going to press.

IBTs in Development

Information on IBT in development is ever-changing. If you know of any inaccuracies in -- or omissions from -- this list, please send an e-mail to richard.jefferys@verizon.net.