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3. Preclinical Models Must Integrate Immune
Compatibility

The problem of tolerization doesn’t begin in Phase III.
It begins much earlier—in the lab, at the moment a
molecule is first nominated for development.

Right now, most biologics enter the pipeline based on a
familiar pair of criteria: binding strength and pathway
specificity. Can it hit the target? Can it block the signal? If
the answer is yes, the molecule moves forward.

But that ignores the deeper question: Can the immune
system live with this molecule?

In most preclinical programs, the immune system is a late-
stage consideration. Immunogenicity isn’t actively screened
for. Dendritic cell activation isn’t modeled. Regulatory T
cell recruitment isn’t tracked. Instead, the assumption is
that tolerization, if it happens, can be managed later—with
dose escalation, co-therapy, or just another switch.

This isn’t just a scientific blind spot.
It’s a missed opportunity to design out failure before it
begins.

To change that, we need to bring immune modeling into
preclinical development—not as a post-hoc safety screen,
but as a core design principle.

Here’s what that looks like:

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