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ADAs accumulate, plasma cells form, and just like that:
tolerance.

We knew this could happen. Scientists warned of
immunogenicity from the beginning. But the response was
not to redesign the drugs. It was to build around the
problem.

Developers first introduced Fc modifications, chemical
masks to the receptors of our immune cells, to reduce
immune activation. Then they began adding
immunosuppressants like Otrexup to mask rejection. But
these were patches, not solutions. Rarely did the field ask
the deeper question: How can we design biologics the
immune system is more likely to tolerate?

Why not?

Because the incentives were aligned for speed, scale, and
regulatory approval—not long-term compatibility. Adding
immunological engineering to a drug candidate meant
higher costs, longer development cycles, and new clinical
risks. And since the system didn’t demand immune
durability as a prerequisite for approval, most companies
didn’t invest in it.

Even where innovation did occur—in oral delivery
platforms or tolerogenic adjuvants designed to teach the
immune system acceptance—those efforts were often
sidelined. Not because they lacked promise, but because
they didn’t fit the established model of success.
Incorporating than cost significant money. Money that
developers are terrified they won’t see profit on.

In a system built around speed to market and monoclonal
dominance, platforms that offered durability over

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