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Engineered chimeric fusion protein compositions and methods of use thereof

A technology of fusion protein and composition, applied in obstacles, one purpose is to use myeloid cells to promote, destroy the integrity of nucleic acid and make gene transfer into these cells an inefficient field, able to solve the obstacles of viral transduction, not applicable issues of gene transmission

Pending Publication Date: 2022-02-18
MYELOID THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Viral transduction of these cells is hampered because macrophages are terminal-stage cells that typically do not divide; therefore, some vectors that rely on integration into the replicating genome have had limited success
In addition, macrophages are very sensitive to "danger signals", so some original viral vectors used for gene transfer induce potent antiviral responses in these cells, making these vectors unsuitable for gene delivery

Method used

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  • Engineered chimeric fusion protein compositions and methods of use thereof
  • Engineered chimeric fusion protein compositions and methods of use thereof
  • Engineered chimeric fusion protein compositions and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0449] The preparation method of CAR-P comprises the following steps: (1) screening PSR subunit framework; (2) screening antigen binding specificity; (3) CAR-P recombinant nucleic acid construct; (4) engineered cells and verification.

[0450] Screening for PSR subunit frameworks: As described above, receptors were designed to include at least one phagocytic receptor domain capable of enhancing signaling for phagocytosis. Essentially, a large number of plasma membrane proteins can be screened for novel phagocytosis function or enhancing domains. Methods of screening for phagocyte receptor subunits are known to those skilled in the art. Additional information can be found in the Examples section. Generally speaking, functional genomics and reverse engineering are usually used to obtain gene sequences encoding functionally related protein polypeptides or parts thereof. In some embodiments, primers and probes are constructed for the identification and / or isolation of proteins, ...

Embodiment approach

[0751] 1. A composition comprising a recombinant nucleic acid encoding a phagocyte or a tethered receptor (PR) fusion protein (PFP), said phagocytic cell or a tethered receptor (PR) fusion protein (PFP) comprising: (a) A PR subunit comprising: (i) a transmembrane domain, and (ii) an intracellular domain comprising an intracellular signaling domain; (b) comprising an antigen binding domain specific for a target cell antigen wherein the transmembrane domain and the extracellular domain are operably linked; and wherein when the PFP binds to an antigen of the target cell, it is associated with a cell that does not express the PFP Compared, the killing or phagocytic activity of cells expressing said PFP is increased by at least greater than 20%.

[0752] 2. The composition of embodiment 1, wherein the intracellular signaling domain is derived from a phagocyte or a tethered receptor, or wherein the intracellular signaling domain comprises a phagocytosis activation domain.

[0753] ...

Embodiment 1

[0980] Example 1. Generation of Novel Chimeric Receptor Fusion Protein (CFP) Constructs

[0981] In this section, exemplary designs for identifying useful CFP ECD, TM, ICD and antigen-binding domains for generating novel CFPs are described. Briefly, a large number of potential candidate proteins were screened for enhanced phagocytic properties and their respective phagocytosis-related intracellular signaling. The useful domains are then used to generate novel CFPs. Screening can be divided into two parts: A. Screening of PR domain; B. Screening of extracellular antigen-binding domain.

[0982] Screening for PR domains:

[0983] 5,800 plasma membrane proteins were screened for their phagocytic potential. J774 macrophages were transiently transfected with a library of 5800 plasma proteins. High-throughput multiplex assays (ranging from 6-well plate assay set-up to 384-well plate assays with robotic handling) were established to assess various potential functions of the p...

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Abstract

The present disclosure provides compositions and methods for making and using engineered phagocytic cells that express a chimeric antigen receptor having an enhanced phagocytic activity for immunotherapy in cancer or infection.

Description

[0001] cross reference [0002] This application claims U.S. Provisional Application No. 62 / 841,190, filed April 30, 2019, U.S. Provisional Application No. 62 / 841,183, filed April 30, 2019, U.S. Non-Provisional Application No. 16 / , filed March 23, 2020 827,381 and the benefit of U.S. Nonprovisional Application No. 16 / 827,302, filed March 23, 2020, each of which is incorporated herein by reference in its entirety. Background technique [0003] Cellular immunotherapy is a promising new technology for fighting difficult-to-treat diseases such as cancer and persistent infections, as well as certain diseases that are refractory to other forms of treatment. A major breakthrough was the discovery of CAR-T cells and their potential use in immunotherapy. CAR-T cells are T lymphocytes that express chimeric antigen receptors that help target T cells to specific diseased cells, such as cancer cells, and depend on the intracellular domain and Coexpressed immunosuppressive cytokines can ...

Claims

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Application Information

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IPC IPC(8): A61K35/15
CPCA61K31/7088A61K38/19A61K9/0019C07K2319/03C07K2317/622C07K16/2896C07K16/32C07K2319/033C07K14/7051A61P35/00A61K2239/38A61K2239/31A61K39/4622A61K39/464402A61K39/464406A61K39/464461A61K39/4631A61K39/464466A61K39/4614A61K2239/48A61K2300/00A61K39/4633A61K39/464474A61K2039/5154A61K2039/5156A61K48/005A61K38/1774A61K39/3955C07K16/00A61K2039/505C07K2317/73
Inventor 丹尼尔·盖茨王宇枭
Owner MYELOID THERAPEUTICS INC
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