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Chimeric cytokine receptors including TGFB binding domains

A technology for binding domains and cytokines, applied in the field of chimeric cytokine receptors including TGFβ binding domains, which can solve the problems of accelerating the rejection of CAR-T cells, affecting the therapeutic effect, toxicity, etc.

Pending Publication Date: 2022-04-12
ALLOGENE THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because cytokines have pleiotropic effects and can also affect the function of other cell types, systemic administration of CAR-T cells or generation of immune-enhancing cytokines has at least two major disadvantages: (i) these approaches may lead to systemic toxicity in humans, and (ii) in the context of allogeneic CAR-T cell therapy, these approaches may lead to bystander host immune activation that accelerates rejection of the allogeneic CAR-T cells, thereby affecting treatment Effect
A limitation of this approach is that the strength of signal 3 depends on the strength of CAR activation

Method used

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  • Chimeric cytokine receptors including TGFB binding domains
  • Chimeric cytokine receptors including TGFB binding domains
  • Chimeric cytokine receptors including TGFB binding domains

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0215] Example 1: Creation of Chimeric Cytokine Receptor-CAR Constructs with Dominant Negative Truncations of TGFβR1 or TGFβR2 build and test

[0216] figure 1 A schematic diagram of an inducible chimeric cytokine receptor of the present disclosure is shown. To couple simultaneous TGF-β binding to cytokine signaling, chimeric cytokine receptors were constructed consisting of: (i) a binding domain comprising the extracellular domain of the TGF-β receptor part or TGF-beta antigen binding domain; (ii) transmembrane domain, said transmembrane domain has intracellular portion, said intracellular portion has JAK2 activation domain; and (iii) STAT recruitment domain, so The STAT recruitment domains include the Stat recruitment (Stat activation) domain from the cytokine receptor tail (cell tail). Such as figure 1 As shown by way of example in , the binding domain includes the extracellular domain of TGFβR2.

[0217] Using a HEK293T cell reporter gene assay, the inducibility ...

example 2

[0221] Example 2: Design and testing of inducible chimeric cytokine receptors using TGFβR2

[0222] as reference figure 1 Briefly described, a chimeric cytokine receptor having a binding domain derived from TGFβR2 (“TGFβR2 chimeric cytokine receptor”) was constructed. To investigate the utility of the TGFβR2 chimeric cytokine receptor in the context of CAR-T cells, variants of the extracellular domain (ECD) of TGFβR2 and variants of the transmembrane (TM) domain of TPOR were constructed. Fusions of each TGFβR2 ECD variant, each TPOR™ domain variant, and the intracellular domain (ICD) of the desired cytokine receptor were cloned into a lentiviral vector encoding a second-generation EGFRvIII-specific CAR ( 2173 scFv; described in Sci Transl Med, 2015 Feb 18;7(275):275ra22), and these receptor variants were tested for activity. To allow stoichiometric co-expression of the chimeric cytokine receptor and CAR, the two genes were linked via the P2A peptide ("chimeric cytokine re...

example 3

[0227] Example 3: Modification of Chimeric Cytokine Receptor Binding Domain and Measurement of Constructed Chimeric Cytokine Receptors try

[0228] In the absence of TGFβR2, TGFβR1 interacts with TGF-β ligands with very low affinity. Once the ECD of TGFβR2 binds the TGF-β ligand, the binary complex has an extended interface to efficiently recruit TGFβR1, thereby forming a ternary complex. Engineered TGFβR2 chimeric cytokine receptors can also bind to endogenous TGFβR1, which can sterically interfere with intended signaling through the cytokine receptor ICD. To eliminate the interaction between the TGFβR2 chimeric cytokine receptor and TGFβR1, several variants of the TGFβR1 cassette were designed and modifications that could enhance cytokine signaling while inhibiting TGF-β signaling were identified.

[0229] Figures 6A-6C Inhibition of TGF-β signaling by expression of chimeric cytokine receptors constructed from TGFβR2 with modifications is shown. Figure 6A A schemati...

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Abstract

Provided herein are chimeric cytokine receptors having a binding domain capable of binding to a TGF-beta ligand or a TGF-beta receptor antibody. When such receptors are present on immune cells (CAR-T cells) with chimeric antigen receptors (CARs), such receptors constitutively and / or by binding of TGF-beta ligands or TGF-beta receptor antibodies increase the expansion, activity and persistence of the CAR-T cells. The invention also provides methods of making and using the chimeric cytokine receptors described herein.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority of U.S. Provisional Application No. 62 / 894,658, filed August 30, 2019; and U.S. Provisional Application No. 63 / 053,322, filed July 17, 2020, both U.S. The content of the provisional application is hereby incorporated by reference in its entirety. [0003] sequence listing [0004] This application is electronically filed via EFS-Web and contains the electronically filed Sequence Listing in .txt format. The .txt file contains a sequence listing named "AT-030_03WO_SL.txt" created on August 27, 2020, and is 576,780 bytes in size. The sequence listing contained in this .txt file is part of the specification and is hereby incorporated by reference in its entirety. technical field Background technique [0005] Adoptive transfer of immune cells (eg, T cells) genetically modified to recognize malignancy-associated antigens is showing promise as a new approach to treating ca...

Claims

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Application Information

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IPC IPC(8): C07K19/00C12N15/62C12N5/10C12N15/867A61K39/00A61P35/00
CPCC07K14/71A61P43/00C07K14/715C07K2319/03C12N5/0636A61K39/464403A61K39/464404A61K39/4611A61K39/464416A61K39/4631C07K2319/70C12N2740/15043C12N15/86C07K16/22C07K14/7051A61P35/00C07K2317/622C12N2510/00A61K35/17
Inventor R·J·林T·J·范布拉康S·帕诺斯基郎姗姗B·J·萨苏
Owner ALLOGENE THERAPEUTICS INC
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