Off-Target Screening of Biotherapeutics

Biotherapeutics cross-reactivity

Toxicity due to cross-reactivity – or “off-target” binding – involving either cell surface or secreted proteins is a serious cause for concern in drug development. Furthermore, demonstrating on-target specificity is a necessary hurdle in the race for regulatory approval for a novel biotherapeutic.

Retrogenix’s Cell Microarray screening provides an understanding of the off-target profile of a biologic candidate during discovery and early development. Building a picture of a biotherapeutic’s ‘toxic liability’ through cross-reactivity screening helps reduce risk through more informed safety assessment and can save considerable time and resources by allowing bad drugs to fail earlier. Retrogenix’s cross-reactivity screening data have been used extensively in regulatory IND and BLA submissions, where high confidence in the specificity of a novel biotherapeutic is required.

Where Retrogenix results have been used in regulatory submissions:

  • Cross-reactivity data were accepted globally. IND or BLA submissions have been made to: US FDA, EMA (Europe), PMDA (Japan) & NMPA (China)
  • Over a third of submissions that included Retrogenix’s cross reactivity results relied solely on these data for specificity assessment, with no tissue cross-reactivity (TCR) studies performed in 38% of cases
  • 90% of submissions using Retrogenix data have been approved to date.

More details on the use of Retrogenix’s IND-enabling specificity data can be found in our regulatory submissions survey results.

Retrogenix off target profiling:

  • The only platform for assessing for off-targets against both plasma membrane and secreted proteins that are expressed in human cells
  • Highly specific with very low numbers of false positives/negatives
  • Can predict/explain reduced bioavailability due to off-target binding
  • Can inform pre-clinical tox model selection, reducing animal testing
  • Helps prioritise drug leads or avoid off-target activities in next-generation of molecules

Low false positive rate

Our highly specific screen typically reports one or two confirmed interactions rather than 100s of erroneous results that can often be seen with protein microarrays. This saves months of validation work following cross-reactivity screening and avoids unnecessary investigations that could stall progress with regulatory submissions.

Please contact us to discuss off-target profiling for lead selection, or an IND-enabling specificity project:

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Screen for cross-reactivity of:

  • Antibodies & bispecifics
  • ADCs
  • ScFvs, Fabs or antibody derivatives
  • Whole CAR T cells
  • Peptides
  • Protein ligands
  • Labelled small molecules

Retrogenix data in regulatory applications

To help understand the role of Retrogenix’s IND-enabling specificity assessment, and to quantify the extent to which it is replacing methods such as tissue cross reactivity (TCR) screening, we undertook a survey to find out how recently screened biotherapeutics are progressing. Pharma, biotech and non-profit sponsors who have undertaken at least one cross-reactivity screening project in the past two years were surveyed – read more here:

See survey results

 

Correcting specificity in an antibody therapeutic

A recent publication describes how an anti-PD1 antibody, which caused the unique side-effect of capillary hemangioma in early phase clinical studies, was screened using Retrogenix technology and found to bind to off-target receptors that are biologically relevant to the formation of hemangioma. Subsequent molecular remodelling of the antibody not only eradicated the in vitro off-target binding but also led to increased potency in PD1/PD-L1 blockade…

Read the case study

Talk to us about a project

    The high quality results generated by Retrogenix will provide important data that will strongly support our future IND submissions.
    R&D Associate, Celyad
    Read more on specificity data for INDs
    Simcere logo
    Aveo Oncology - The Human Response
    Theraclone Sciences
    BioInvent
    AstraZeneca
    Bluebird Bio
    glycotope_logo
    The Center for Infectious Disease Research
    Compugen Logo
    Sanofi Logo
    The University of Copenhagen
    Lund University
    MedImmune
    NIH - National Institutes of Health
    The University of Pennsylvania
    Scripps Florida - The Scripps Research Institute
    Peptinnovate Ltd - Unlocking Nature's Potential
    The University of Sheffield
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    Unum Theraputics Logo
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