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Generated: August 25, 2019

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Claims for Patent: 8,802,374

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Summary for Patent: 8,802,374
Title:Truncated epiderimal growth factor receptor (EGFRt) for transduced T cell selection
Abstract: A non-immunogenic selection epitope may be generated by removing certain amino acid sequences of the protein. For example, a gene encoding a truncated human epidermal growth factor receptor polypeptide (EGFRt) that lacks the membrane distal EGF-binding domain and the cytoplasmic signaling tail, but retains an extracellular epitope recognized by an anti-EGFR antibody is provided. Cells may be genetically modified to express EGFRt and then purified without the immunoactivity that would accompany the use of full-length EGFR immunoactivity. Through flow cytometric analysis, EGFRt was successfully utilized as an in vivo tracking marker for genetically modified human T cell engraftment in mice. Furthermore, EGFRt was demonstrated to have cellular depletion potential through cetuximab mediated antibody dependent cellular cytotoxicity (ADCC) pathways. Thus, EGFRt may be used as a non-immunogenic selection tool, tracking marker, a depletion tool or a suicide gene for genetically modified cells having therapeutic potential.
Inventor(s): Jensen; Michael C. (Bainbridge Island, WA)
Assignee: City of Hope (Duarte, CA)
Application Number:13/463,247
Patent Claims:1. A genetically modified Epidermal Growth Factor Receptor (EGFR) gene, comprising a nucleotide sequence encoding a truncated non-immunogenic endogenous cell surface molecule, said cell surface molecule comprising an EGFR Domain III and an EGFR Domain IV; but lacking nucleotides all of the domains consisting of an EGFR Domain I, an EGFR Domain II, an EGFR Juxtamembrane Domain, and an EGFR Tyrosine Kinase Domain; wherein the truncated non-immunogenic endogenous cell surface molecule (i) does not have endogenous signaling or trafficking function; (ii) binds a therapeutic anti-EGFR antibody; (iii) does not bind an endogenous EGFR ligand; and (iv) acts as a marker.

2. The gene of claim 1, further comprising a GMCSFR alpha chain signal sequence.

3. The gene of claim 2 comprising SEQ ID NO:2.

4. The gene of claim 2, wherein the gene encodes an amino acid sequence comprising at least 90% identical to SEQ ID NO:3.

5. The gene of claim 2, wherein the gene encodes an amino acid sequence comprising SEQ ID NO:3.

6. The gene of claim 1, wherein the gene is part of a construct which comprises the modified EGFR coupled via a C-terminal 2A cleavable linker to a chimeric antigen receptor specific for a tumor associated antigen selected from CD19, a codon-optimized anti-CD19 costimulatory chimeric antigen receptor (CD19CAR), CD20 or CD22.

7. The gene of claim 6, wherein the modified EGFR is coupled to a CD19CAR and a C-terminal 2A cleavable linker.

8. The gene of claim 1, comprising nucleotides 67-1071 of SEQ ID NO:2.

9. The gene of claim 1, comprising nucleotides 67-1071 of SEQ ID NO:1.

10. The gene of claim 2 comprising SEQ ID NO:1.

11. The gene of claim 1, wherein the gene encodes an amino acid sequence comprising residues 23-357 of SEQ ID NO:2.

12. A modified EGFR gene coupled to a CD19CAR and a C-terminal 2A cleavable linker, wherein the gene encodes an amino acid sequence comprising SEQ ID NO:6.

13. The modified EGFR gene of claim 1, wherein the marker is used to enrich cells.

14. The modified EGFR gene of claim 1, wherein the marker is used to select cells.

15. The modified EGFR gene of claim 1, wherein the marker is used to induce cell suicide in cells expressing the truncated non-immunogenic endogenous cell surface molecule.

16. The modified EGFR gene of claim 1, wherein the endogenous EGFR ligand is EGF.

17. The modified EGFR gene of claim 1, wherein the therapeutic anti-EGFR antibody is cetuximab.

18. A genetically modified Epidermal Growth Factor Receptor (EGFR) gene, comprising a nucleotide sequence encoding a truncated non-immunogenic endogenous cell surface molecule, said cell surface molecule comprising an EGFR Domain III and an EGFR Domain IV; but lacking nucleotides all of the domains consisting of an EGFR Domain I, an EGFR Domain II, an EGFR Juxtamembrane Domain, and an EGFR Tyrosine Kinase Domain; wherein the truncated non-immunogenic endogenous cell surface molecule (i) does not contain endogenous signaling or trafficking function; (ii) binds a therapeutic anti-EGFR antibody; (iii) does not bind an endogenous EGFR ligand; and (iv) acts as a marker used to enrich cells, select cells, or induce cell suicide in cells expressing said cell surface molecule.

19. The modified EGFR gene of claim 18, wherein the endogenous EGFR ligand is EGF.

20. The modified EGFR gene of claim 18, wherein the therapeutic anti-EGFR antibody is cetuximab.

Details for Patent 8,802,374

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Imclone ERBITUX cetuximab VIAL; INTRAVENOUS 125084 001 2004-06-18   Try a Free Trial City of Hope (Duarte, CA) 2029-11-03 RX Orphan search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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International Patent Family for US Patent 8,802,374

Country Patent Number Publication Date
World Intellectual Property Organization (WIPO) 2011056894 May 12, 2011
World Intellectual Property Organization (WIPO) 2011056894 Nov 24, 2011
United States of America 10100281 Oct 16, 2018
United States of America 2012301447 Nov 29, 2012
United States of America 2015184128 Jul 02, 2015
United States of America 2017152480 Jun 01, 2017
>Country >Patent Number >Publication Date

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