IP Library › Granted Patent US 12,577,289
Granted Patent B2
US 12,577,289 · App. 17/479,898 · Granted Mar 17, 2026

Surrogate co-receptors for t cells and methods of use

Inventors: Michael S. Kuhns (Tucson, AZ); Deepta Bhattacharya (Tucson, AZ); Heather Lynn Bronnimann (Tucson, AZ)
Assignee: ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA
C07K14/70539A61K40/11A61K40/31A61K40/32A61K40/40C07K14/705C07K14/7051C12N5/0636C12N9/12C12Y207/10002C07K2319/02C07K2319/03C07K2319/74
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Quick Facts
Patent No.
US 12,577,289
App. No.
17/479,898
Granted
Mar 17, 2026
Kind
B2
Abstract

Surrogate co-receptors for T cells, including T cells expressing chimeric receptors comprising major histocompatibility molecules grafted onto T cell receptor molecules. The surrogate co-receptors feature a portion of CD8, wherein the Ig domains of CD8 are replaced with Ig domains that confer novel specificities (e.g. antibody Fv fragments specific for a target of interest.) The surrogate co-receptors may be used to help enhance CRM pMHC -CD3 signaling as part of a 5-module receptor system. The present invention also describes Lck fusions.

Claims (23)

1 . A surrogate co-receptor (SCoR) comprising a first chain comprising: a portion of a T-cell co-receptor linked to a C-terminal of a first binding portion, wherein the portion of the T-cell co-receptor comprises at least a portion of a CD8 chain, a portion of a CD4 chain or a combination thereof, wherein the first binding portion is an Ig domain against a particular target expressed on a surface of a target cell.

2 . The SCoR of claim 1 further comprising a second chain comprising a portion of a T-cell co-receptor linked to a C-terminal of a second binding portion, wherein the portion of the T-cell co-receptor comprises at least a portion of a CD8 chain, a portion of a CD4 chain or a combination thereof, wherein the second binding portion is an Ig domain against a particular target expressed on a surface of a target cell, wherein the second chain of the SCoR is linked to the first chain of the SCoR via a disulfide bond between an extracellular domain (ECD) portion of the T-cell co-receptor of the first chain and an ECD portion of the T-cell co-receptor of the second chain.

3 . The SCoR of claim 1 , wherein the CD8 chain comprises a CD8α chain, a CD8β chain or a combination thereof.

4 . The SCoR of claim 1 , wherein the CD8 chain or the CD4 chain comprises a portion of an extracellular domain (ECD), a portion of a transmembrane domain (TMD), a portion of an intracellular domain (ICD), or a combination thereof.

5 . The SCoR of claim 4 , wherein the ECD of CD4 comprises a D1 domain, a D2 domain, a D3 domain, a D4 domain, or a combination thereof.

6 . The SCoR of claim 5 , wherein the first binding portion replaces the D1 domain of the ECD.

7 . The SCoR of claim 1 , wherein the portion of the CD8 or the portion of the CD4 chain further comprise a Lck protein fused to or replacing an intracellular domain (ICD).

8 . The SCoR of claim 1 , wherein the portion of the CD8 or the portion of the CD4 are directly linked or indirectly linked to the respective binding portions.

9 . The SCoR of claim 1 , wherein the Ig domains are from a CD80 ligand binding region, a CD86 ligand binding region, or a combination thereof.

10 . The SCoR of claim 1 , wherein the Ig domains are antibody fragments.

11 . The SCoR of claim 10 , wherein the antibody fragments are antibody Fv fragments, wherein the antibody Fv fragments are heavy chain domains, light chain domains, or a combination thereof.

12 . An engineered cell expressing on its surface at least one surrogate co-receptor according to claim 1 .

13 . An engineered cell co-expressing on its surface:

a. at least one chimeric receptor (CRM) comprising (i) a class I major histocompatibility complex (MHC) portion comprised of at least a portion of an extracellular domain of a class I MHC protein, a beta2 microglobulin and a targeted peptide fused to the N-terminal of a T cell receptor (TCR) portion, comprised of at least a portion of a transmembrane domain and at least a portion of a cytoplasmic domain of a TCR protein; or (ii) a class II MHC portion comprised of at least a portion of an extracellular domain of a class II MHC protein and a targeted peptide fused to the N-terminal of a TCR portion comprises of at least portion of a transmembrane domain and at least a portion of a cytoplasmic domain of a TCR protein;

wherein in (i) and (ii), first the targeted peptide of the MHC portion is presented in the MHC (pMHC), second the pMHC is specific for a first epitope of a TCR, third the pMHC can complex with said TCR; and

b. at least one SCoR according to claim 1 , wherein the SCoR is specific for a second epitope of the TCR.

14 . The engineered cell of claim 13 , wherein the MHC portion is indirectly or directly fused to the TCR portion.

15 . The engineered cell of claim 13 , wherein the TCR portion further comprises at least a portion of an extracellular domain of the TCR protein.

16 . The engineered cell of claim 13 , wherein the targeted peptide is integrated into the MHC portion, or directly or indirectly fused to the MHC portion.

17 . The engineered cell of claim 13 , wherein the MHC protein comprises HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB, H2-Aa, H2-B1, H2-K1, H2-EB beta, H2-EK alpha, H2-EK beta, a fragment thereof, or a combination thereof.

18 . The engineered cell of claim 13 , wherein the TCR protein comprises TRAC, TRBC1, TRBC2, TRDC, TRGC1, TRGC2, TCRA, TCB1, TCB2, TCC1, TCC2, TCC3, TCC4, a fragment thereof, or a combination thereof.

19 . A method of eliminating or redirecting a target cell, said method comprising introducing a genetically engineered cell according to claim 13 , wherein the CRM of the genetically engineered cell is specific for a TCR of the target cell, wherein upon binding of the CRM of the genetically engineered cell to the TCR of the target cell, the genetically engineered cell (a) initiates a signaling cascade that eliminates the target cell, or (b) instructs the target cell to differentiate to a specific effector function.

20 . A surrogate co-receptor (SCoR) comprising a first chain comprising: a portion of a T-cell co-receptor linked to a C-terminal of a first binding portion, wherein the portion of the T-cell co-receptor comprises at least a portion of a CD8 chain, a portion of a CD4 chain or a combination thereof, wherein the first binding portion is an Ig domain against a particular target, wherein the portion of the CD8 or the portion of the CD4 chain further comprise a Lck protein fused to or replacing an intracellular domain (ICD).

Assignments (2)
CONFIRMATORY LICENSE Recorded Jan 17, 2024
From: UNIVERSITY OF ARIZONA
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 066338/0957 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 24, 2021
From: KUHNS, MICHAEL S.; BHATTACHARYA, DEEPTA; BRONNIMANN, HEATHER LYNN
To: ARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA
Reel/Frame 058208/0522 →
Continuity (6)
Continuation In Part PCTUS2020023942 · Mar 20, 2020
Continuation In Part 17345425 · Jun 11, 2021
Division 15738467
Provisional Application 62821222 · Mar 20, 2019
Provisional Application 62186865 · Jun 30, 2015
Related Publication 20220002379A1 · Jan 6, 2022
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