Systems and methods for assessing modulators of immune checkpoints

Patent metadata

Field	Value
Publication number	US-2016169869-A1
Application number	US-201514947660-A
Country	US
Kind code	A1
Filing date	Nov 20, 2015
Priority date	Nov 20, 2014
Publication date	Jun 16, 2016
Grant date	—

Abstract

Provided herein are compositions, systems, and methods for assessing modulators of immune checkpoints. In particular, artificial antigen presenting cells (aAPCs) and immune effector cells are provided to assess the potency of test agents to inhibit immune checkpoints.

First claim

1 . A composition comprising an artificial antigen presenting cell (aAPC) or phospholipid droplet displaying on its surface a T cell receptor (TCR) activator and an immune checkpoint ligand (ICL).

2 .- 3 . (canceled)

4 . The composition of claim 1 , wherein the TCR activator is an anti-cluster of differentiation 3 (CD3) antibody, or an antibody fragment thereof, or major histocompatibility complex (MHC).

5 . The composition of claim 1 , wherein the ICL is selected from the group consisting of PD-L1, PD-L2, B7-H4, CD155, galectin-9, and HVEM.

6 . (canceled)

7 . A system comprising:
(a) an effector cell displaying on its surface an immune checkpoint receptor (ICR), and comprising a T cell receptor (TCR); and (b) an artificial antigen presenting cell (aAPC) or phospholipid droplet displaying on its surface a T cell receptor (TCR) activator and an immune checkpoint ligand (ICL); wherein the ICR and ICL form an ICR/ICL complex upon interaction.

8 . The system of claim 7 , wherein formation of the ICR/ICL complex results in modulation of TCR activation by the TCR activator and/or modulation of one or more TCR-dependent pathways.

9 . The system of claim 8 , wherein modulation comprises:
(a) inhibition of TCR activation by the TCR activator and/or one or more TCR-dependent pathways; or (b) enhancement of TCR activation by the TCR activator and/or one or more TCR-dependent pathways.

10 . The system of claim 7 , wherein the TCR activator is an anti-cluster-of-differentiation-3 (CD3) antibody, or an antibody fragment thereof, or major histocompatibility complex (MHC).

11 . The system of claim 7 , wherein the ICL is selected from the group consisting of CD80/86 PD-L1, PD-L2, B7-H4, CD155, galectin-9, and HVEM.

12 . The system of claim 7 , wherein the ICR is selected from the group consisting of PD-1, CTLA-4, LAG-3, TIM-3, CD160, TIGIT, IL-10 receptor, and BTLA.

13 . The system of claim 7 , wherein the effector cell is selected from T cells including Jurkat, HuT-78, CEM, Molt-4 and primary T cells.

14 . The system of claim 7 , wherein the effector cell further comprises a reporter of: TCR activation, TCR pathway activation, and/or ICR/ICL complex modulation of TCR activation or TCR pathway activation.

15 .- 16 . (canceled)

17 . The system of claim 14 , wherein the reporter is a natural reporter, intrinsic to the effector cell type, having a characteristic that is detectable and correlates to TCR activation, TCR pathway activation, and/or ICR/ICL complex modulation of TCR activation or TCR pathway activation.

18 . The system of claim 14 , wherein the reporter is an artificial reporter, exogenous to the effector cell type, having a characteristic that is detectable and correlates to TCR activation, TCR pathway activation, and/or ICR/ICL complex modulation of TCR activation or TCR pathway activation.

19 . The system of claim 18 , wherein the reporter is a gene, the expression of which is under the control of TCR-pathway-dependent reporter.

20 . The system of claim 19 , wherein the TCR-pathway-dependent reporter is a nuclear factor of activated T cells (NFAT) promoter.

21 . (canceled)

22 . The system of claim 7 , further comprising a blockade agent or test blockade agent.

23 . The system of claim 22 , wherein the blockade agent inhibits formation of the ICR/ICL complex, resulting in modulation of TCR activation or TCR pathway activation.

24 .- 28 . (canceled)

29 . A method comprising:
(a) forming a system comprising:
(i) an effector cell displaying on its surface an immune checkpoint receptor (ICR), and comprising a T Cell Receptor (TCR) and a TCR-pathway-dependent reporter, and
(ii) an artificial antigen presenting cell (aAPC) displaying on its surface a TCR activator and an immune checkpoint ligand (ICL); wherein the ICR and ICL form an ICR/ICL complex upon interaction, and wherein formation of the ICR/ICL complex results in modulation of TCR activation by the TCR activator and/or modulation of one or more TCR-dependent pathways; and
(b) detecting said TCR-pathway-dependent reporter or a signal from said reporter.

30 . The method of claim 29 , further comprising adding to the system a blockade agent, wherein the blockade agent inhibits formation of the ICR/ICL complex or inhibits ICR/ICL-dependent modulation of TCR activation by the TCR activator and/or modulation of one or more TCR-dependent pathways.

31 . The method of claim 30 , wherein said TCR-pathway-dependent reporter or a signal from said reporter is detected: (1) before, (2) concurrent with, and/or (3) after addition of said blockade agent, and further comprising a step of comparing signal from (1) before, (2) concurrent with, and/or (3) after addition of said blockade agent to determine the effect of the blockade agent.

32 .- 39 . (canceled)

Assignees

• Promega Corp

Inventors

• Cong Mei
• Cheng Zhijie Jey
• Karassina Natasha
• Grailer Jamison
• Fan Frank

Classifications

• C07K16/2803

  against the immunoglobulin superfamily · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K16/2809 Primary

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

• G01N33/5041 Primary

  involving analysis of members of signalling pathways · CPC title

• G01N2333/70532

  B7 molecules, e.g. CD80, CD86 · CPC title