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Salvage chimeric antigen receptor systems

A technology of chimeric antigen receptors and antigens, applied in improved compositions, cell immunotherapy compositions, and the field of cancer treatment, which can solve limited efficacy, disappointing clinical activity and relapsed or refractory cancers, poor pharmacokinetics characteristic curve etc.

Inactive Publication Date: 2019-02-05
2SEVENTY BIO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Immunotherapy with therapeutic antibodies has also had limited success, due in part to poor pharmacokinetic profiles, rapid antibody elimination by serum proteases and filtration at the glomeruli, and limited penetration into tumor sites and the ability of target antigens to Tumor cells express limited levels of
Attempts to use genetically modified cells expressing chimeric antigen receptors (CARs) have also had limited success due to poor in vivo expansion of CAR T cells, rapid loss of cells following infusion, disappointing clinical activity and relapsed or refractory cancer

Method used

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  • Salvage chimeric antigen receptor systems
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  • Salvage chimeric antigen receptor systems

Examples

Experimental program
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Effect test

example 1

[0545] Rescue CAR system

[0546] A functional salvage CAR system uses a dimerizable anti-CD19 salvage receptor and bridging factor AP21967 to redirect anti-BCMA salvage CAR to the CD19-positive, BCMA-negative Nalm-6 cell line.

[0547] The control anti-BCMA CAR contained a CD8α-derived signal peptide, an anti-BCMA scFv, a CD8α-derived hinge region and transmembrane domain, an intracellular 4-1BB co-stimulatory domain, and a CD3ζ signaling domain ( figure 1 , left panel, SEQ ID NO.1). Anti-BCMA rescue CAR contains CD8α-derived signal peptide, anti-BCMA scFv, G4S linker sequence, FRB variant (T82L), CD8α-derived hinge region and transmembrane domain, intracellular 4-1BB co-stimulatory domain, and CD3ζ signaling domain ( figure 1 , central panel, SEQ ID NO.2). The dimerizable salvage receptor comprises an IgK-derived signal peptide, FLAG tag, anti-CD19 scFv and FKBP12 domain (SEQ ID NO: 3). The polypeptide used in this experiment was a polyprotein (SEQ ID NO: 4) also conta...

example 2

[0557] Preloaded Dimerizable Anti-CD19 Salvage Receptor

[0558] A stable 293T cell line (293T-707) expressing a dimerizable anti-CD19 salvage receptor comprising a human lipid delivery was generated using a lentivirus encoding a dimerizable anti-CD19 salvage receptor Protein-2 derived signal peptide, scFv targeting CD19 antigen, FKBP12 domain, T2A.1 sequence, mCherry sequence and woodchuck post-transcriptional regulatory region (WPRE) (SEQ ID NO: 5).

[0559] The dimeric anti-CD19 salvage receptor was purified by collecting and filtering (0.22 μm filter) 500 mL of 293T-707 cell culture supernatant and binding to a FKBP12 specific affinity column. The column was generated by incubating 2 mL of NeutrAvidin Agarose (Thermo Fisher) with 400 μg Biotin-FK506 for 30 min at room temperature under constant rotation. The column was washed with PBS to remove uncoupled biotin-FK506. The filtered 293T-707 supernatant was passed through the column by gravity. Wash the column with PBS un...

example 3

[0562] Preloaded Dimerizable Anti-CD19 Salvage Receptor Redirected Anti-BCMA Salvage CAR

[0563] T cells were transduced with lentiviral vectors encoding anti-BCMA CAR or anti-BCMA salvage CAR. CAR T cells were compared with GFP-expressing CD19-positive Nalm-6 cells and A 50:50 mixture of BFP-expressing CD19-negative K562 cells was co-cultured for 24 hr. Anti-BCMA rescue CAR T cells display CD19-specific cytotoxicity against Nalm-6 in the presence of a dimerizable anti-CD19 rescue receptor preloaded with rapamycin. Figure 5 . AP21967 is not required to trigger CD19-specific cytotoxicity.

[0564] Anti-BCMA salvage CAR T was administered at reduced amounts (125ng, 62.5ng, 31.3ng, 15.6ng, 7.8ng, 3.9ng, 2.0ng) of preloaded dimerizable anti-CD19 salvage receptors at a 2:1 E:T ratio Cells were co-cultured for 24 hr with a 50:50 mixture of GFP-expressing CD19-positive Nalm-6 cells and BFP-expressing CD19-negative K562 cells. As little as 2 ng of preloaded dimeric anti-CD19 sa...

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Abstract

The invention provides improved compositions for adoptive cell therapies for cancers. The invention generally provides improved vectors for generating T cell therapies and methods of using the same. More particularly, the invention provides salvage CARs, dimerizable salvage receptors, and their use in treating, preventing, or ameliorating cancers, and in particular preferred embodiments relapsed or refractory cancer. In various embodiments, a salvage chimeric antigen receptor (CAR) is provided comprising: an extracellular antigen binding domain; a multimerization domain; a transmembrane domain; one or more intracellular co-stimulatory signaling domains; and / or a primary signaling domain.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 356,335, filed June 29, 2016, and U.S. Provisional Application No. 62 / 322,634, filed April 14, 2016, under 35 U.S.C. § 119(e), which Each of the applications is incorporated herein by reference in its entirety. [0003] Statement Regarding the Sequence Listing [0004] The Sequence Listing associated with this application is provided in text format instead of a paper copy and is hereby incorporated by reference into this specification. The name of the text file containing the sequence listing is BLBD_068_02WO_ST25.txt. The text file is 42KB, created on April 14, 2017, and submitted electronically via the EFS website at the same time as the specification submission. technical field [0005] The present invention relates to improved compositions and methods for treating cancer. More specifically, the present invention relates to cellular immu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/705C07K14/725C07K16/28C07K19/00C12N15/62
CPCC07K14/705C07K19/00C12N15/62C07K16/2803C07K16/2878C07K2317/622C07K2319/02C07K2319/03C07K2319/33A61P35/00A61P35/02A61P43/00A61K39/464417A61K39/4611A61K39/4631A61K39/464412C07K14/7051C07K14/70517C07K14/70578A61K35/17
Inventor 梁炜亨
Owner 2SEVENTY BIO INC
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