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The result? A pipeline that produced therapies that
worked beautifully—until they didn’t.

And when they stopped working, the failure wasn’t framed
as tolerization. It was called “secondary non-response.”
“Loss of efficacy.” “Treatment resistance.” Euphemisms
that obscured the real issue: the immune system had
decided the drug no longer belonged.

This chapter explores how we got here. Not through
negligence, but through structural drift—through choices
that made sense in isolation but collectively produced a
system that accepts failure as routine. We’ll trace the
origins of biologics, the regulatory shortcuts, the clinical
workarounds, the market forces, and the scientific silos that
allowed tolerization to become normalized.

Because the crisis of biologic durability didn’t come from a
single decision.

It came from all the places no one thought to look.

2.1 – From Chemistry to Biology:

The Birth of Biologics

For much of the 20th century, medicine was a chemistry
problem—and the pharmaceutical industry was built to
solve it with remarkable success. The foundational tools of
modern drug discovery were chemical structures, reaction
pathways, and the periodic table. The goal was clear:
identify molecular targets, synthesize compounds to
modulate them, and optimize for potency, absorption, and

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