The Discovery

Bristow discovered that the blood protein α1Proteinase Inhibitor (α1PI, α1antitrypsin, AAT) regulates the number of CD4 T cells that are produced by the thymus and that the mechanism involves locomotion of immature T cells through the thymus.

In pathological conditions, α1PI is inactivated by inflammation-related or infection-related enzymes and, as a result, immune cell locomotion halts precisely at the site of infection or inflammation.

It was shown in clinical situations where CD4 T cell numbers were excessively low, treatment with α1PI elevated CD4 T cell numbers. Secondary immunodeficiency in which CD4 T cell numbers are excessively low includes most forms of cancer, HIV/AIDS, and malnutrition.

With collaborators at CSL Behring and at Grifols, Bristow showed in 2 successful clinical trials that the ratio of immunocompetent CD4 T cells increased in HIV infected and uninfected patients within 2 weeks of initiating α1PI therapy. Unlike all other attempts to increase the number of CD4 T cells (e.g. IL-2), there were no adverse effects of treatment because α1PI is the natural regulator of CD4 T cell numbers.

The Problem

There is insufficient quantity of α1PI to provide therapy for the number of patients with cancer. In addition, the cost and inconvenience of treatment procedures to the patient and health care provider mandates the development of an orally-available, small molecule to act as a surrogate for the protein α1PI.