High affinity t cell receptors and uses thereof

Patent metadata

Field	Value
Publication number	US-2018369280-A1
Application number	US-201616064161-A
Country	US
Kind code	A1
Filing date	Dec 23, 2016
Priority date	Dec 23, 2015
Publication date	Dec 27, 2018
Grant date	—

Abstract

The present disclosure provides TCRs with high or enhanced affinity against various tumor associated antigens (including human Wilms tumor protein 1 (WT 1) epitopes and mesothelin epitopes), T cells expressing such high affinity antigen specific TCRs, nucleic acids encoding the same, and compositions for use in treating diseases or disorders in which cells overexpress one or more of these antigens, such as in cancer.

First claim

What is claimed is:

1 . A binding protein, comprising:
(a) a T cell receptor (TCR) α-chain variable (V α ) domain having a CDR3 amino acid sequence shown in any one of SEQ ID NOS.:93-102, and a TCR β-chain variable (V β ) domain; or (b) a V α domain of (a) and a V β domain having a CDR3 amino acid sequence shown in any one of SEQ ID NOS.:105-114; wherein the binding protein is capable of specifically binding to a WT-1 peptide:HLA complex on a cell surface independent of CD8 or in the absence of CD8.

2 . The binding protein according to claim 1 , wherein the binding protein is capable of specifically binding to a VLDFAPPGA (SEQ ID NO.:117):human leukocyte antigen (HLA) complex with a K d less than or equal to about 10 −8 M.

3 . The binding protein according to claim 1 or claim 2 , wherein the binding protein comprises a V α domain that is at least about 90% identical to an amino acid sequence as set forth in any one of SEQ ID NOS.:19, 26, 33, 40, 47, 54, 63, 70, 77 and 84, and comprises a V β domain that is at least about 90% identical to the amino acid sequence as set forth in any one of SEQ ID NOS.:22, 29, 36, 43, 50, 57, 66, 73, 80 and 87, provided that (a) at least three or four of the CDRs have no change in sequence, wherein the CDRs that do have sequence changes have only up to two amino acid substitutions, up to a contiguous five amino acid deletion, or a combination thereof, and (b) the binding protein remains capable of specifically binding to a WT-1 peptide:HLA cell surface complex independent, or in the absence, of CD8.

4 . The binding protein according to any one of claims 1 - 3 , wherein the binding protein specifically binds to a VLDFAPPGA (SEQ ID NO.:117):HLA-A*201 complex.

5 . The binding protein according to any one of claims 1 - 4 , wherein the V α domain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:19, 26, 33, 40 or 47.

6 . The binding protein according to any one of claims 1 - 4 , wherein the V α domain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:54, 63, 70, 77, or 84.

7 . The binding protein according to any one of claims 1 - 6 , wherein the V β domain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:22, 29, 36, 43, or 50.

8 . The binding protein according to any one of claims 1 - 6 , wherein the V β domain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:57, 66, 73, 80, or 87.

9 . The binding protein according to any one of claims 1 - 8 , wherein the V α domain comprises an α-chain constant domain having at least 90% sequence identity to an amino acid sequence as set forth in SEQ ID NO.:2 or 3.

10 . The binding protein according to any one of claims 1 - 9 , wherein the V β domain comprises a β-chain constant domain having at least 90% sequence identity to an amino acid sequence as set forth in SEQ ID NO.:7, 8, 58 or 59.

11 . The binding protein according to any one of claims 1 - 10 , wherein the binding protein comprises a TCR α-chain having an amino acid sequence as set forth in any one of SEQ ID NOS.:20, 27, 34, 41, 48, 55, 64, 71, 78 and 85, and a TCR β-chain having an amino acid sequence as set forth in any one of SEQ ID NOS.:23, 30, 37, 44, 51, 60, 67, 74, 81 and 88.

12 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:20, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:23.

13 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:27, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:30.

14 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:34, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:37.

15 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:41, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:44.

16 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:48, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:51.

17 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:55, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:60.

18 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:64, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:67.

19 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:71, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:74.

20 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:78, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:81.

21 . The binding protein according to claim 11 , wherein the TCR α-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:85, and the TCR β-chain comprises or consists of an amino acid sequence as set forth in SEQ ID NO.:88.

22 . The binding protein according to any one of claims 1 - 21 , wherein the binding protein is a T cell receptor (TCR), an antigen-binding fragment of a TCR, or a chimeric antigen receptor.

23 . The binding protein according to claim 22 , wherein the TCR, the chimeric antigen receptor or the antigen-binding fragment of the TCR is chimeric, humanized or human.

24 . The binding protein according to claim 22 or 23 , wherein the antigen-binding fragment of the TCR comprises a single chain TCR (scTCR).

25 . The binding protein according to any one of claims 22 - 24 , wherein the binding protein is a chimeric antigen receptor.

26 . The binding protein according to any one of claims 22 - 24 , wherein the binding protein is a TCR.

27 . A binding protein, comprising:
(a) a T cell receptor (TCR) α-chain variable (V α ) domain having a CDR3 amino acid sequence shown in SEQ ID NO.:91 or 92, and a TCR β-chain variable (V β ) domain; or (b) a V α domain of (a) and a V β domain having a CDR3 amino acid sequence shown in SEQ ID NO.:103 or 104; wherein the binding protein is capable of specifically binding to a mesothelin peptide:HLA complex on a cell surface independent, or in the absence, of CD8.

28 . The binding protein according to claim 27 , wherein the binding protein is capable of specifically binding to a SLLFLLFSL (SEQ ID NO.:115):human leukocyte antigen (HLA) complex or a VLPLTVAEV (SEQ ID NO.:116):human leukocyte antigen (HLA) complex with a K d less than or equal to about 10 −8 M.

29 . The binding protein accordin

Assignees

• Hutchinson Fred Cancer Res
• Adaptive Biotechnologies Corp

Inventors

• Schmitt Thomas M
• Greenberg Philip D
• Chapuis Aude G
• Robins Harlan S
• Sherwood Anna M

Classifications

• A61P35/02

  specific for leukemia · CPC title

• C07K14/7051

  T-cell receptor (TcR)-CD3 complex · CPC title

• A61K38/20

  Interleukins [IL] · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title