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Looking for Winners

To determine the biological activity of his molecules, Smith collaborated with Cindy Jacobs in Immunex’s preclinical labs. Jacobs had joined Immunex in 1985 as a part-time scientist while she was still in medical school and initially supported the GMCSF and interleukin projects (17). Jacobs, who held a PhD in veterinary pathology/ microbiology, set up animal models to test the efficacy of the soluble IL-1 receptor and TNFR:Fc. Each of the molecules was effective in animal models of antigeninduced arthritis, and they were more effective given together than either one alone (15). TNFR:Fc also protected mice from otherwise lethal injections of lipopolysaccharide, an animal model of sepsis (14). Using radiolabeled TNFR:Fc, Jacobs followed its pharmacokinetics and distribution in serial blood and tissue sections collected from the animals. She found that TNFR:Fc had a 5-fold longer serum half-life than the soluble p75 receptor (14, 15). Smith and Jacobs moved quickly to secure Immunex’s patent rights to TNFR:Fc (16).

Despite Duzan’s efforts, GM-CSF’s flagging sales disappointed investors. At the same time, Immunex’s research expenditures were, if anything, increasing. In 1993-1994, in rapid succession, American Cyanamid acquired majority ownership of Immunex, and then American Home Products purchased American Cyanamid (2). In parallel, clinical trial results indicated that PIXY 321 was ineffective – a crushing blow to both the clinical team and the new managing partners. In October 1993, the project team shut down the PIXY 321 program (6). Immunex researchers continued interleukin development, exploring the soluble IL-1 receptor for asthma/allergy, rheumatoid arthritis, and inflammatory bowel disease (15). Preliminary clinical trials showed that the molecule protected healthy volunteers from a cutaneous allergic challenge (18). With TNFR:Fc, the animal model results justified clinical trials in several therapeutic areas, but Immunex’s decision makers gave sepsis top priority.

Reprinted from Therapeutics and Clinical Risk Management at http://bit.ly/2zrhOO2 with permission from Dove Medical Press.

Assessing Activity

Figure 1: Etanercept structure in comparison with other TNF antagonists.

Reprinted from The Pharmacologist • December 2017

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2018 Special Compilation Issue of The Pharmacologist  

ASPET is pleased to present the second in a series of special editions of our quarterly news magazine, The Pharmacologist. This special com...

2018 Special Compilation Issue of The Pharmacologist  

ASPET is pleased to present the second in a series of special editions of our quarterly news magazine, The Pharmacologist. This special com...