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21 March 2022

Choose targets with low risk of side effects pinpointed by Ardigen's ARDitox platform

Case Study

High accuracy in silico predictions for selecting the right target epitopes

Our platform provides the ability to identify and inspect putative cross-reactive epitopes that can lead to off-target toxicity.
Consideration of the entire human proteome, extended to include frequent single nucleotide polymorphisms, ensures that the
entire relevant space of peptides can be searched.

Our interactive dashboard allows you to examine each identified cross-reactive epitope, its presentation probability,
expression profile, and safety score.

Affinity-enhanced T-cells, directed against MAGEA3 epitope (EVDPIGHLY) presented on HLA-A*01:01, caused the death of two patients
due to the off-target toxicity effects against a cross-reactive epitope derived from titin (TTN, ESDPIVAQY). Although the
T-cells were
thoroughly tested on multiple cell lines, including muscles, this cross-reactive epitope was overlooked because TTN
is only expressed
in contracting muscles. With Ardigen’s ARDitox platform, the TTN epitope was identified with the lowest
possible safety score and
visualizations were generated showing in which tissues it is expressed.

Our client provided us with information on two genetically modified T-cells directed against cancer cells. Both had well-defined target
peptides with their corresponding HLA types. For one of them, we identified 97 potential off-targets and marked 3 as
completely unsafe
and requiring further experimental validation. The one that appeared to expose the real danger was with
9 amino acids, of which 4 differ
from the target itself. The off-target peptide was not previously detected in empirical studies.
We achieved this after following several
consecutive steps: identification of off-target sequences (even those that differ significantly
from the target), expansion of cross-reactive
epitopes by including frequent SNPs, selection of presented epitopes using
ARDisplay (our in-house deep learning model), safety ranking
of off-target epitopes based on amino acid physico-chemical
properties, and additional analysis of mRNA and peptide tissue-specific

The Ardigen’s ARDitox platform results were further validated in vitro, confirming that one of the aforementioned offtargets
has the potential to generate immuno-toxicity.

Value we deliver:
  1. Identification of immuno-toxicities caused by allogeneic HLA reactivity
  2. Incorporation of results from X-scan to increase specificity towards given target peptide
  3. Increased treatment safety with the evaluation of a large space of possible off-targets
  4. Identification of cross-reactive epitopes that differ significantly from the target epitope
  5. Identification of epitopes not expressed in cell lines but present in functional tissues
  6. Inclusion of frequent variants that are not present in the reference proteome
  7. User-friendly dashboard with the possibility of generating esthetic figures
  8. Additional safety net before entering clinical studies
  9. Possibility of further collaboration on TCR optimization
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