Элзокабтаген автолейцел

Rec. INN (наименование, зарегистрированное ВОЗ)

autologous T lymphocytes from peripheral blood obtained by leukapheresis, transduced with four self-inactivating, non- replicating lentiviral vectors encoding (i) a chimeric antigen receptor (CAR) targeting guanylyl cyclase C (GC-C, GUCY2C), (ii) a chimeric antigen receptor (CAR) targeting CD19 co-expressing interferon gamma (IFN-γ), (iii) a chimeric antigen receptor (CAR) targeting CD19 co-expressing interleukin-6 (IL-6), (iv) a chimeric antigen receptor (CAR) targeting CD19 co-expressing interleukin- 12 (IL-12) fused to a von Hippel-Lindau tumour suppressor (VHL) recognition sequence.
Each CAR transgene comprises a signal peptide derived from the CD8 alpha chain, a single chain variable fragment (scFv) binding domain, a CD8 hinge and transmembrane domain, a 4-1BB co- stimulatory domain and a CD3ζ signalling domain, under control of the human elongation factor 1 alpha (EF-1α) core promoter. For the three vectors that also encode a cytokine, each cytokine gene is preceded by an NFAT enhancer and is under the control of a minimal IL-2 promoter. For the IL-12-VHL expressing vector, a recognition sequence of the von Hippel-Lindau tumour suppressor protein (VHL) is fused to the 3' end of the IL-12 gene via an EA rich linker.
Each construct is flanked by 5' and 3' long terminal repeats (LTRs) and also contains a ψ packaging signal, a Rev response element (RRE), a central polypurine tract (CPPT) and central termination sequence (CTS) and a Woodchuck hepatitis virus post- transcriptional regulatory element (WPRE). Each vector is pseudotyped with the vesicular stomatitis virus (VSV) G envelope protein.
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 with serum replacement and interleukin 2 (IL- 2). The T lymphocytes (>75%) are positive for the transgenes (>5% CAR positive), with less than 0.5 % CD19+ cells. The cells produce cytokines (interleukin-6, interleukin-12, and interferon gamma) in co-culture with B lymphocytes

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