Unlock instant, AI-driven research and patent intelligence for your innovation.

Enhanced chimeric antigen receptors and use thereof

a technology of chimeric antigen receptor and enhanced chimeric antigen, applied in the field of immunology and molecular biology, can solve the problems of affecting the full use of this approach in cancer treatment, poor prognosis, and many patients' inability to cur

Pending Publication Date: 2021-08-19
BOARD OF RGT THE UNIV OF TEXAS SYST
View PDF0 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent provides enhanced chimeric antigen receptors (CARs) and methods of using them for the treatment of diseases and disorders such as cancer and autoimmune disorders. The CARs comprise a truncated EGFRvIII, which does not contain an EGF binding domain, and a hinge region that links an extracellular domain and at least one intracellular immune signaling domain. The Ev3 hinge has at least 80% sequence identity to SEQ ID NO:2. The CARs can be used to detect and ablate CAR-expressing cells. The Ev3 hinge does not contain EGF binding domain. The at least one signaling domain comprises CD. The technical effects of this patent are improved CARs for better treatment of cancer and autoimmune disorders.

Problems solved by technology

Despite technological advancements in the diagnosis and treatment options available to patients diagnosed with cancer, the prognosis still often remains poor and many patients cannot be cured.
However, many drawbacks in the clinical use of immune cells therapy impair the full use of this approach in cancer treatments.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Enhanced chimeric antigen receptors and use thereof
  • Enhanced chimeric antigen receptors and use thereof
  • Enhanced chimeric antigen receptors and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

nt of Truncated EGFRvIII (Ev3) CAR

[0231]An Ev3-CAR was designed in which the Ev3 stalk serves as an integrative structure to transduce signals from antigen binding, such as by scFv, as well as an “off” switch, meaning it can be recognized by clinically accessible antibodies such as cetuximab to ablate CAR-positive immune cells (FIG. 1A). The Ev3-CAR may further comprise DAP12 signaling domain and is designated Ev3-DAP12-CAR. A schematic depicting Ev3 as compared to EGFR which comprise the endodomain and the EGF binding domain is shown in FIG. 2.

[0232]Retroviral vectors encoding the Ev3-CAR or Ev3-DAP12-CAR with various antigen binding domains were generated as depicted in FIGS. 3A-3D. The antigen-binding domain was both the scFv derived from the mouse anti-human antibody as well as a humanized scFv. The vectors comprise CD28 and CD3ζ signaling domains and, optionally, DAP12. The vectors also comprise a suicide gene, inducible caspase 9.

[0233]The CD19-specific CARs including CAR19.Ev...

example 2

nt of Humanized CARs

[0234]A platform was developed to generate humanized scFvs for use in producing humanized CARs. Due to structural constraints, some residues contribute more to antigen binding, thus 3-D modeling was used to identify potentially critical interactions to generate the humanized CARs. The stepwise process detailed below may be repeated iteratively to improve on previous cycles.

[0235]The CAR humanization workflow provided herein comprises 5 basic process modules as detailed below and depicted in FIG. 5A.

[0236]Module I comprises monoclonal antibody (mAb) sequence analysis. The BLAST program was harnessed in search of immunoglobulin (IG) sequences for the best match against the starting queries, such as the murine mAb sequences (FIG. 5B). BLAST can analyze nucleotide and amino acid sequences, either in series (one-by-one) or in parallel (in batches), as well as search against germline gene databases including curated sequence databases simultaneously thus maximizing the...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
Fractionaaaaaaaaaa
Fractionaaaaaaaaaa
Fractionaaaaaaaaaa
Login to View More

Abstract

Provided herein are chimeric antigen receptors (CARs) comprising a truncated EGFRvIII (Ev3) in the hinge region of the CAR and / or a humanized scFv. Further provided herein are immune cells expressing the CARs as well as methods of their use in the treatment of immune disorders.

Description

[0001]The present application is a continuation of U.S. patent application Ser. No. 16 / 632,762 filed Jan. 21, 2020, which is a national phase application under 35 U.S.C. § 371 that claims priority to International Application No. PCT / US2018 / 043779 filed Jul. 25, 2018, which claims the priority benefit of U.S. Provisional Application Ser. No. 62 / 536,934, filed Jul. 25, 2017, all of which are hereby incorporated by reference in their entirety.INCORPORATION OF SEQUENCE LISTING[0002]The sequence listing that is contained in the file named “MDAC_P1331USC1_1001160638_SL.txt”, which is 289 KB (as measured in Microsoft Windows) and was created on Apr. 16, 2021, is filed herewith by electronic submission and is incorporated by reference herein.BACKGROUND1. Field[0003]The present invention relates generally to the fields of immunology and molecular biology. More particularly, it concerns enhanced chimeric antigen receptors (CARs), such as for immune cells.2. Description of Related Art[0004]De...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07K16/28C07K14/54A61K35/17C07K14/705C07K14/71C07K14/725
CPCC07K16/2896C07K14/5443A61K35/17C07K14/70503C07K14/71C07K14/70521A61K2039/5156C07K16/2803C07K2317/622C07K2319/02C07K2317/24C07K2319/30C07K2319/33C07K14/7051A61K38/00C07K16/2863C07K2317/73C07K2317/76C07K2319/03C12N5/0646C12N2510/00A61K39/464412A61K2239/22A61K2239/48A61K39/4613A61K39/4631A61K2239/17A61K2039/5158A61K2039/572A61P37/06C07K2317/732C12N15/52C12N15/86
Inventor ANG, SONNY OONLIU, ENLISHPALL, ELIZABETHREZVANI, KATY
Owner BOARD OF RGT THE UNIV OF TEXAS SYST