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Chimeric antigen receptors targeting tim-1

A chimeric antigen receptor, TIM-1 technology, applied in the field of preparation and use of such compositions, can solve problems such as not yet achieved success

Active Publication Date: 2019-11-22
CELDARA MEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this approach has shown curative potential in many patients with chemotherapy-refractory hematological malignancies (Kalos et al., SciTransl Med. 2011; 3:95ra73; Maus et al., Cancer Immunol Res. 2013; 1: 26-31; Porter et al., N Engl J Med.2011; 365:725-733), but similar success has not been achieved in solid tumors

Method used

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  • Chimeric antigen receptors targeting tim-1
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  • Chimeric antigen receptors targeting tim-1

Examples

Experimental program
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preparation example Construction

[0289] In some embodiments, the method of preparation includes the step of freezing (eg, cryopreserving) the cells before or after isolation, incubation, and / or engineering. In some embodiments, the step of freezing followed by thawing removes granulocytes, and to some extent monocytes, from the cell population. In some embodiments, cells are suspended in a freezing solution to remove plasma and platelets, eg, after a washing step. In some aspects, any of a variety of known freezing solutions and parameters can be used. One example involves the use of PBS containing 20% ​​DMSO and 8% human serum albumin (HSA), or other suitable cell freezing medium. Then it was diluted 1:1 with culture medium so that the final concentrations of DMSO and HSA were 10% and 4%, respectively. Cells were then frozen to -80°C at a rate of 1°C per minute and stored in the gas phase of liquid nitrogen tanks.

[0290] therapeutic application

[0291] Isolated cells obtained by the methods describe...

Embodiment 1

[0409] Example 1: Design and synthesis of anti-TIM-1 CAR variants

[0410] according to figure 1 General schematic for generation of anti-TIM-1 CAR. For the six variants, Figure 2A A more detailed schematic of the CAR construct is provided. The CAR structure is based on a second generation CAR format (Gacerez et al., J Cell Physiol, 2016 Dec;231(12):2590-8). There are six different TIM-1 -responsive single change variable fragments (scFv) in Hv-linker-Lv or Lv-linker-Hv orientation from anti-TIM1 hybridoma clones 1.29, 2.70.2 or 2.59.2 ( Figure 2B ). These anti-TIM-1 scFvs were formed by fusing the variable domains of the heavy chain (VH) and light chain (VL) domains to the following 15 amino acid glycine (G)-serine (S) linker: (G4S)3 Linker (SEQ ID NO:201), 3 repeats of GGGGS (SEQ ID NO:200). These were cloned individually in frame into the hinge domain containing CD28 (residues 135-152 of CD28 or SEQ ID NO:214), the transmembrane domain of CD28 (residues 153-179 of ...

Embodiment 2

[0417] Example 2: Generation of anti-TIM-1 CAR T cells

[0418] Cell culture and retroviral transduction: The retroviral stocks described above were used using optimized methods (Cubillos-Ruiz et al., Oncotarget 2010; 1:329-33; Huarte et al., Blood 2008; 112:1259-1268 Stephen et al., Immunity 2014;41:427-439), protocols and resources previously developed at Celdara Medical to transduce human T cells from healthy donors.

[0419] For some variants, cell culture, retroviral transduction and purification protocols are summarized in image 3 middle. The resulting transduced cells were analyzed by flow cytometry ( Figure 4 ). For the purification of some variants, the protocol is as follows. Human PBMCs from healthy donors (HemaCare) were the source of T cells for CAR transduction. Donor PBMCs were thawed, reconstituted in complete medium, and pelleted by centrifugation. Cells were then resuspended in complete medium and then activated by incubation with IL-2 and anti-CD3 fo...

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Abstract

The invention provides chimeric antigen receptors (CARs) that specifically bind to the T-cell immunoglobulin and mucin domain 1 (TIM-1) protein. The invention further relates to modified immune cells,e.g., T or NK cells, comprising such CARs, CAR-encoding nucleic acids, CAR-encoding vectors, and methods of making such compositions. The invention further relates to methods for therapeutic use of these CARs and modified immune cells for the treatment of a condition, disorder, or disease associated with cells expressing TIM-1 (e.g., cancer).

Description

[0001] Related application open [0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 445,976, filed January 13, 2017, which is hereby incorporated by reference in its entirety. [0003] sequence public [0004] This application includes as part of its disclosure the Biological Sequence Listing in a file named "56867o1000.txt" and 193,169 bytes in size, created on January 12, 2018, which is hereby incorporated by reference in its entirety enter. technical field [0005] The invention disclosed herein relates to chimeric antigen receptors (CARs) that bind to antigenic T cell immunoglobulin domain and mucin domain 1 (TIM-1 ) proteins and uses of such CARs. In particular, chimeric antigen receptors are provided comprising an antigen binding domain that binds TIM-1, a transmembrane domain, and one or more intracellular signaling domains. The nucleotide sequence encoding the anti-TIM-1 CAR construct and the amino acid sequence comprising the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/30C07K16/28C07K14/705C12N5/0783C12N5/078A61K39/395A61K35/17A61P35/00
CPCA61K35/17A61P35/00C07K14/70521C07K16/2803A61K2039/505A61K2039/5156A61K2039/5158C07K2317/622C07K2317/73C07K2319/03C07K2319/40A61K38/00C07K14/7051C07K16/30C12N15/85
Inventor L-Z·何H·C·小玛什T·凯勒T·A·斯塔德海姆J·M·穆拉德J·雷德尔
Owner CELDARA MEDICAL
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