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stress, diet, or comorbidities played a role. Even when anti-
drug antibodies were detected, they were often framed as
“non-neutralizing” or “clinically insignificant”—technical
labels that softened the implication that the drug had
effectively been rejected.

This framing allowed tolerization to slip below the
threshold of urgency. It became a “clinical reality,” not a
call to action.

And once it was normalized, inertia set in.

No central stakeholder had both the authority
and the incentive to lead a change:

Stakeholder Behavior/Response Underlying Reason
Incentives favored
Profited from patients
Pharma switching therapies, rapid launch and brand
cycling over investing
Companies especially within the same in immunologic
drug portfolio.
redesign.
Lack of consensus on
clinically relevant
Did not enforce standards
Regulators related to immune immunogenicity
thresholds, validated
durability.
biomarkers, or mandate
for long-term data.
Managed immunogenicity Priority was immediate
at the bedside by escalating
Clinicians doses, switching biologics, patient relief rather
than long-term
or adding
immunosuppressants. systemic reform.
Without clear evidence
Covered therapy switches if
Payers the new drug was on that immune durability
impacted efficiency,
formulary.
there was no incentive.

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