Анбалкабтаген аутолейцел

Rec. INN (наименование, зарегистрированное ВОЗ)

autologous T lymphocytes obtained from peripheral blood mononuclear cells by leukapheresis, transduced with a self-inactivating, non-replicating lentiviral vector, encoding a chimeric antigen receptor (CAR) targeting CD19, plus two short hairpin RNAs (shRNA) directed against two immune checkpoint regulators, programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT).
The expressed transgene comprises a CD8α leader sequence, a murine anti-CD19 single chain variable fragment (scFv) (derived from the mouse hybridoma FMC63), a CD8α hinge and transmembrane region, and a 4-1BB (CD137) and CD3ζ (CD247) intracellular signalling domain, and is under control of the elongation factor 1 alpha (EF1α) promoter. The short hairpin RNA shPD-1 targets the 3' untranslated region part of PD-1 mRNA and is under control of a human U6 promoter. The short hairpin RNA shTIGIT targets a coding sequence part of TIGIT mRNA and is under control of a mouse U6 promoter. The construct is flanked by 5' and 3' long terminal repeats (LTRs) and also contains an HIV-1 ψ packaging signal, a Rev response element (RRE), a central polypurine tract (cPPT) and a Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE).
The leukapheresis material is enriched for CD4/CD8 T lymphocytes by positive immunoselection, activated by CD3 and CD28 agonists and transduced with the vector. The cells are then expanded in media containing serum replacement and interleukin 2 (IL-2). The T lymphocytes (≥97.8%) are positive for the transgene (≥11.0% CAR positive), secrete interferon gamma, and demonstrate knockdown of PD-1 (≥33.7%) or TIGIT (≥83.5%).

Поделиться этой страницей