Immunotoxicology has advanced considerably since
its early beginnings in immunosuppression of toxic
chemicals. This is evident by the many research areas
in immunotoxicology that span the spectrum from
immunosuppression to immunostimulation and others that
cross both spectra and are simply "immunomodulatory".
Although we have advanced the science of understanding
immune systems, our nonclinical models for risk assessment
of immunotoxicology of compounds destined for human
exposure are only partially successful.
Current regulation regarding immunomodulatory
changes for pharmaceuticals relies on an older 2002
FDA Immunotoxicology Guidance (for US products)
or the ICH S8 Guidance for products worldwide. The
Guidances do cover immunosuppression, immunogenicity/
antigenicity, and hypersensitivity somewhat thoroughly.
For immunosuppression, there are many pathways
for evaluation that rely both on cellular evaluations
(e.g., cell counts, percentage of subtypes) as well as
functional effects. The most common assay for evaluating
functional effects is the TDAR (T-cell Dependent Antibody
Response). There are multiple protocols for the TDAR,but most utilize KLH (Keyhole Limpet Hemocyanin) or
SRBC (Sheep Red Blood Cells) as an antigen with or
without drug exposure. The TDAR is relatively good
at predicting strongly immunotoxic compounds, but
weaker compounds or non-suppressive compounds
(e.g., immunomodulatory or immunostimulating) are
not usually detected using the TDAR. Immunogenicity
is commonly covered by ICH S6 guidance for biologic
compounds and is somewhat specific for biologic
products. Drug products may cause immunogenicity, but
not commonly unless adducts or haptenization occurs.
Hypersentivity is commonly assessed using the LLNA
(local lymph node assay) in rodents. Similar to the TDAR,
it is effective for strongly reactive compounds, but weaker
compounds are not readily detectible using this assay.
Although these Guidances do an adequate job discussing
immunosuppressive compounds or hypersensitivity,
they do not adequately cover immunomodulatory or
immunostimulatory compounds. This is not a fault of the
Guidances but is the product of the advancement in the
science over time.
For example, although we have evidence of multiple
products that cause autoimmunity, we do not have an
adequate nonclinical model for evaluating autoimmunity
prior to administering drugs to humans. This leads to a
lapse in safety evaluation due to the lack of an adequate
model for testing. Similarly, we know that compounds
can stimulate immune responses. For example, the nowfamous
TGN-1412 only marginal effects in nonclinical
models, but caused serious adverse effects clinically.
The drug was an IgG4 monoclonal antibody which pan activated
T-cells. Patients administered the drug had
severe cytokine activation and cascade or the widely used "cytokine storm". In the several years since this clinical
effect, marginal success has been made advancing the
models to predict these effect nonclinically. However, the
Guidances regulating these products has not advanced.
In conclusion, the current Guidances for Immunotoxicology
appear to be lagging behind the science. It would be
suggested that cooperation between the regulators,
industry, and academia identify the current state of the
science for assessing immunomodulatory effects and set
a plan for updating the current Guidances. Furthermore,
research gaps can be identified, further supporting areas
for research that could benefit all parties.