Нендокабтаген оногедлейцел

Prop. INN (наименование, предложенное ВОЗ)

allogeneic T lymphocytes obtained from peripheral blood mononuclear cells by leukapheresis of healthy volunteer donors, transduced with a self-inactivating, non-replicating lentiviral vector encoding a chimeric antigen receptor (CAR) targeting human B-cell maturation antigen (BCMA). The cells are also genetically modified using transcription activator-like (TAL) effector nucleases that are transiently delivered into the cell as mRNAs via electroporation and code for two pairs: one pair is designed for disruption of the T-cell receptor α constant (TRAC) and the other for disruption of the CD52 locus.
The expressed transgene comprises a human CD8α leader sequence, an anti-BCMA single chain variable fragment (scFv) derived from the anti-human BCMA (clone P5A2), a CD8α hinge and transmembrane domain, and 4-1BB (CD137) and CD3ζ (CD247) intracellular costimulatory domains, under control of the human elongation factor 1 alpha (EF1α) promoter. The extracellular region of the CAR also contains 2 mimotopes that confer susceptibility to rituximab. The construct is flanked by 5' and 3' long terminal repeats (LTRs) and also contains a ψ packaging signal, a truncated gag, a Rev response element (RRE), a central polypurine tract (cPPT) sequence and a mutated Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE). The vector is pseudotyped with vesicular stomatitis virus (VSV) glycoprotein G.
The leukapheresis material is activated by CD3 and CD28 agonists to stimulate T lymphocyte growth in media containing serum and interleukin 2 (IL-2), transduced with the lentiviral vector, genetically modified, and then culture expanded. At the end of expansion, TCR- cells are enriched by positive selection and residual TCR+ cells are depleted using magnetic bead purification. The T lymphocytes consist of ≥20% TCR αβ- T lymphocytes expressing the CAR-BCMA transgene, ≥50% CD52- and ≤3.0% TCR αβ+ T lymphocytes. The cells respond to BCMA-expressing target cells by releasing interferon gamma (IFN-γ) and demonstrate cytotoxicity against cells expressing BCMA

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