TNX-355, a Monoclonal Antibody Entry Inhibitor Candidate, Tries to Replicate Early Success

by Chael Needle

[Treatment Horizons]

At the Tenth Conference on Retroviruses and Opportunistic Infections last February, Tanox, Inc., reported the results of its Phase Ia trial of TNX-355, an anti-CD4 humanized monoclonal antibody which has been in-licensed from Biogen.

TNX-355, designed to directly block cellular infection with HIV by binding to the CD4 receptor on host cell surfaces, would fall into a new class of drugs called entry inhibitors. After TNX-355 showed some success in in vitro and animal studies, it moved on to a human safety trial, which demonstrated that the candidate is well-tolerated and showed a significant decrease in viral load in patients, most of whom had failed two HAART regimens. Preclinical studies showed that the candidate does not suppress immune function and does not deplete CD4 cells.

Now in Phase Ib trials, researchers are looking at multiple dosing schedules for TNX-355 and continuing to monitor its safety. While the single-dose Phase Ia trial lasted a month, the range of dosing time and frequency for patients in Phase Ib trials ?more closely mimics what a real regimen might look like,? says Dr. Ashraf Hanna, Ph.D., M.D., Vice President of Strategic Planning at Tanox. He notes that the study should be completed by the end of the year and the data available in early 2004. The initial trial looked at patients who had failed conventional therapy because of drug resistance or for other reasons. Researchers, however, do not know yet if TNX-355 can specifically target any particular drug-resistant HIV.

Optimal dosing will ultimately be resolved in Phase II, but researchers have an idea that the IV infusions will be on a weekly or monthly schedule. ?Interpreting the Phase Ia data, I think we can say that dosing won?t be daily,? notes Dr. Hanna. ?The Phase Ia data showed a drop in viral load that?depending on the dose?remained down for fourteen to twenty-one days. If one dose knocks down the virus for twenty-one, or fourteen, days, then perhaps you give the second dose roughly around that time.?

Though TNX-355 is being looked at as a treatment for HIV, Tanox has long looked at the uses of monoclonal antibodies for a range of conditions. Tanox was founded in the late eighties by Harvard-trained Drs. Tse Wen and Nancy T. Chang. As professors at Baylor University, they came to focus on monoclonal antibodies, especially their role in treating asthma and allergy. Eighteen years later, Xolair became the first Tanox-produced drug in this class.

The production of monoclonal antibodies is a generic process, says Dr. Hanna, and starts with finding one that you think works the way you want it to work. ?You take whatever you want your antibody to work against: say, human hair, and place a piece of human hair into a mouse. The mouse sees it as foreign and makes millions of different kinds of antibodies against that human hair. We take those antibodies from the mouse, separate them, and find one that has the properties we want: One perhaps binds to blonde hair only, or brunette hair?you can do all these tests on mouse antibodies until you figure out the one that has the right binding properties.?

The initial drug, Dr. Hanna says, is produced through a process called humanization: ?You take that mouse antibody and, except for the very little ends of it that need to bind, change the rest of the antibody into a human structure. That?s how the initial drug is made.? Once identified, researchers work backwards, taking the DNA that produces the antibody and placing it in cells which are then cultured so that the cells produce the antibodies. Mass production of these cells ensues and the desired antibodies are extracted.

Satisfied with the results of the Phase Ia trial, Tanox is committed to going ahead with an efficacy trial?as long as the candidate remains safe. While Tanox has been looking at TNX-355 as a treatment for HIV, the question of its use as a preventative hovers nearby. ?The method of action, which is blocking CD4 entry, makes certain physiological sense as a prophylactic,? says Dr. Hanna. ?Our antibody binds to the cells and protects the cells from HIV entering, so, if you have this drug in you and you are exposed, there would be good reason to think you would not be infected. The path now is to do the testing for treatment.?

For more information about enrolling in this trial, please visit www.tanox.com.

Chael Needle wrote about microbicides in the September 2003 issue.

October 2003