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Chimeric receptor polypeptides in combination with trans metabolism molecules modulating intracellular lactate concentrations and therapeutic uses thereof

A chimeric receptor, regulatory factor technology, used in fusion polypeptides, for targeting specific cell fusion, growth factors/growth regulators, etc.

Pending Publication Date: 2021-06-01
ソティオリミティドライアビリティカンパニー
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Cell-based immunotherapy, while promising, faces challenges arising from the specific properties of the tumor microenvironment (TME), the cellular environment created by the interaction between malignant cells and non-transformed cells

Method used

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  • Chimeric receptor polypeptides in combination with trans metabolism molecules modulating intracellular lactate concentrations and therapeutic uses thereof
  • Chimeric receptor polypeptides in combination with trans metabolism molecules modulating intracellular lactate concentrations and therapeutic uses thereof
  • Chimeric receptor polypeptides in combination with trans metabolism molecules modulating intracellular lactate concentrations and therapeutic uses thereof

Examples

Experimental program
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example

[0129] In other embodiments, the extracellular antigen binding domain of any of the CAR polypeptides described herein can be specific for a pathogenic antigen, such as a bacterial, viral, or fungal antigen. Some examples are provided below: influenza virus neuraminidase, hemagglutinin or M2 protein, human respiratory syncytial virus (RSV) F or G glycoprotein, herpes simplex virus glycoprotein gB, gC, gD or gE, Chlamydia MOMP or PorB protein, dengue virus core protein, matrix protein or glycoprotein E, measles virus hemagglutinin, herpes simplex virus type 2 glycoprotein gB, poliovirus I VP1, envelope glycoprotein of HIV 1, B Hepatitis core antigen or surface antigen, diphtheria toxin, streptococcal 24M epitope, gonococcal pili protein, pseudorabies virus g50 (gpD), pseudorabies virus II (gpB), pseudorabies virus III (gpC), pseudorabies virus sugar Protein H, pseudorabies virus glycoprotein E, transmissible gastroenteritis glycoprotein 195, transmissible gastroenteritis matrix ...

Embodiment 1

[0494] Example 1: Effect of reduced glucose concentration on T cell function

[0495] A γ-retrovirus encoding an exemplary GPC3-targeting CAR expression construct of SEQ ID NO: 97 was generated by recombinant technology and used to infect primary human T cells to produce cells expressing the target on their cell surface. cells to the CAR polypeptide of GPC3. A six-day flow-based proliferation assay was then used to test the functionality of CAR-expressing cells targeting GPC3. Specifically, 200,000 non-transduced mock T cells or T cells expressing a CAR construct targeting GPC3 were mixed with 50,000 GPC3+ hepatocellular carcinoma JHH7 tumor cells or Hep3B tumor cells at a ratio of 4:1 (effector cells / CAR-expressing The ratio of T cells to target cells) was incubated together. In the presence of different concentrations of glucose, the co-culture was incubated at 37 °C in 5% CO 2 Incubate for six days in the incubator. At the end of six days, co-cultures were harvested and...

Embodiment 2

[0496] Example 2: Effect of expressing lactate regulatory factors on T cell function when using GPC3-targeting CAR-T expression constructs

[0497]A gamma retrovirus encoding an exemplary GPC3-targeting CAR polypeptide expression construct (SEQ ID NO:97) was produced by recombinant technology and used to infect primary human T cells to produce Cells expressing CAR polypeptides targeting GPC3. In addition, gamma coding for exemplary GPC3-targeting CAR polypeptides (SEQ ID NO:97 or 98) and lactate transporting polypeptides (MCT1, MCT2 or MCT4) (SEQ ID NO:82 to SEQ ID NO:84) were produced by recombinant technology A retroviral vector was used to infect primary human T cells to generate cells expressing a GPC3-targeting polypeptide and a lactate-regulating factor (eg, polypeptide). In constructs encoding both the CAR polypeptide and the lactate regulator, the two polypeptides are separated by a P2A ribosomal skipping sequence. The variants expressed are CARs in combination with ...

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Abstract

Disclosed herein are genetically engineered hematopoietic cells, which express one or more lactate-modulating factors (e.g., polypeptides), and optionally a chimeric receptor polypeptide (e.g., an antibody-coupled T cell receptor (ACTR) polypeptide or a chimeric antigen receptor (CAR) polypeptide) capable of binding to a target antigen of interest. Also disclosed herein are uses of the engineered hematopoietic cells for inhibiting cells expressing a target antigen in a subject in need thereof.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of the filing dates of U.S. Provisional Application No. 62 / 728,338, filed September 7, 2018, and U.S. Provisional Application No. 62 / 728,306, filed September 7, 2018. The entire contents of each of these prior applications are incorporated herein by reference. Background technique [0003] Cancer immunotherapy, including cell-based therapies, is used to elicit an immune response that attacks tumor cells while sparing normal tissue. It is a promising option for the treatment of various types of cancer because of its potential to evade genetic and cellular mechanisms of drug resistance and target tumor cells while sparing normal tissue. [0004] Cell-based therapies may involve cytotoxic T cells whose reactivity is biased towards cancer cells. Eshhar et al., Proc.Natl.Acad.Sci.U.S.A.; 1993; 90(2):720-724; Geiger et al., J Immunol.1999; 162(10):5931-5939; Brentjens et al., Nat.Med 2003...

Claims

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Application Information

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IPC IPC(8): C12N15/52C12N15/62C12N15/63
CPCC07K14/705C12N5/0636C07K2319/03C07K14/7051C12Y101/01027C12Y207/11002C12N2510/00C12N2501/515C12N2501/51C12N2501/52C12N2500/34A61K39/464474A61K39/4632A61K2239/59A61K39/4631A61K39/4611C12N5/0646C12N9/0006C12N9/12C07K16/303C07K14/70521C07K14/70578A61P35/00C07K2319/02C07K2317/622C07K2319/30A61K35/17A61K38/1709A61K38/177A61K38/1774A61K38/179A61K39/39558A61K2039/505A61K2039/5156A61K2039/5158C07K14/4702C07K14/70517C07K14/70535C07K14/71C07K2317/53C07K2317/569C07K2319/33C12N7/00C12N15/86C12N2740/15043
Inventor K.麦金尼斯S.埃坦伯格L.巴伦M.弗雷C.威尔逊G.莫茨
Owner ソティオリミティドライアビリティカンパニー
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