Evaluate the specificity of CAR-T cell therapies by screening the human membrane proteome 

Rigorous specificity testing is critical for drug and antibody development, as even minimal off-target binding can lead to serious adverse effects. Cross-reactivity assessment of cytotoxic biotherapeutics, such as CAR-T cell therapies, is imperative since off-target engagement could lead to inappropriate immune cell activation and misdirected cell killing. Since CAR-T therapies engage the target cell by binding to membrane proteins, a complete assessment of cell surface protein interactions is required to assess binding specificity. MPA CART figure_3.7.22 (2)

Comprehensive specificity profiling of novel CAR-T cell therapies is a regulatory requirement. However, CAR-T cells are not amenable to screening using traditional immunohistochemical binding assays.

Integral Molecular’s Membrane Proteome Array (MPA) is the leading solution for profiling specificity of CAR-T cells and other antibody-based therapeutics. The MPA is a cell-based array that contains the largest set of human membrane proteins assembled. It encompasses 95% of the human membrane proteome, allowing for comprehensive cross-reactivity assessment.

Reduce risk of toxicity by identifying potential off-target binding liabilities using the MPA

Specificity testing on the MPA early in development can de-risk CAR-T programs by selecting an scFv candidate without off-target liabilities. MPA cross-reactivity data is also widely accepted in regulatory filings for novel CAR-T cell therapies. The MPA screen is compatible with all antibodies, scFv and Fc-fusion-like compounds, as well as bicistronic CAR constructs. Because the MPA is expressed in live cells, whole CAR-T cells can also be tested using phenotypic screening for binding or activation.

Features of the Membrane Proteome Array

  • 6,000 membrane proteins representing ~95% of the membrane proteome
  • Native-conformation target proteins expressed in live cells, with appropriate post-translational modifications
  • Binding interactions tested using sensitive high-throughput flow cytometry
  • Target validation by secondary titration analysis
  • IND-enabling safety assessment

Case Study

Cabaletta LogoLearn how Cabaletta Bio used the MPA to screen the specificity of their novel T-cell therapeutic, and then successfully file for IND

Autoantibodies against desmoglein 3 (DSG3) cause painful mucosal blisters in mucosal pemphigus vulgaris (mPv). Cabaletta Bio developed DSG3-CAART (Chimeric AutoAntibody Receptor T cell) therapy to eliminate these autoantibodies by targeting the corresponding pool of antigen-specific B cells. To progress the clinical development, Cabaletta Bio needed to demonstrate the specificity of DSG3-CAART and document the lack of off-target interactions for their IND submission.

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Comprehensive Specificity Profiling of Antibody-Based Therapeutics Using the Membrane Proteome Array 

Webinar Agenda

  • Understand how Integral Molecular’s MPA is used to select leads that do not display off-target binding liabilities
  • Learn how cell-array data, such as the MPA screen, supports IND submissions either without or in conjunction with traditional tissue cross-reactivity studies
  • Discover how the MPA was used to rapidly evaluate the specificity of a novel antibody-based SARS-CoV-2 therapeutic

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