Modified gamma delta t cells

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By modifying γδT cells with chimeric antigen receptors and genomic modifications, the method addresses the limitations of existing γδT cell activation and expansion methods, resulting in enhanced antigen-binding and functional properties for immune cell engineering and therapy.

HK40134701APending Publication Date: 2026-07-10POINTLOMA BIOSCIENCES INC

Patent Information

Authority / Receiving Office: HK · HK
Patent Type: Applications
Current Assignee / Owner: POINTLOMA BIOSCIENCES INC
Filing Date: 2026-04-20
Publication Date: 2026-07-10

AI Technical Summary

Technical Problem

Existing methods for activating and expanding γδT cells are limited in their ability to target specific antigens and enhance their functionality, particularly in the context of immune cell engineering and therapeutic applications.

Method used

The method involves modifying γδT cells with chimeric antigen receptors specific for TROP2 and/or PD-L1, and introducing genomic modifications such as TGFβR2 knockout, along with using single-domain antibodies targeting TROP2 and PD-L1, to enhance their antigen-binding capabilities and functional properties.

Benefits of technology

The modified γδT cells exhibit enhanced antigen-binding and functional properties, making them suitable for immune cell engineering and therapeutic applications.

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Abstract

The technology relates in part to methods for activating and expanding multi-subsets of gamma delta T cells. In some aspects, the technology relates to multi-subsets of gamma delta T cells. In some aspects, the technology relates to activated and expanded multi-subsets of gamma delta T cells produced by methods described herein. In some aspects, the multi-subsets of gamma delta T cells are modified. In some aspects, the multi-subsets of gamma delta T cells comprise one or more chimeric antigen receptors. In some aspects, the chimeric antigen receptors comprise one or more antigen binding domains with binding specificity to TROP2 and / or PD-L1. In some aspects, the multi-subsets of gamma delta T cells express IL-15. In some aspects, the multi-subsets of gamma delta T cells comprise one or more genome modifications. In some aspects, the multi-subsets of gamma delta T cells comprise a TGFβR2 knock-out. The technology also relates in part to single-domain antibodies (nanobodies) that target TROP2, PD-L1, or TROP2 and PD-L1, uses for immune cell engineering, pharmaceutical compositions thereof, diagnostic and non-diagnostic reagents thereof, and therapeutic and non-therapeutic methods of use thereof.

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Description

538551\45920052_1.docx IRN: 538551 Title: Modified γδT Cells Abstract: This technique relates in part to methods for activating and expanding multiple subsets of γδT cells. In some aspects, this technique relates to multiple subsets of γδT cells. In some aspects, this technique relates to activated and expanded multiple subsets of γδT cells generated by the methods described herein. In some aspects, the multiple subsets of γδT cells are modified. In some aspects, the multiple subsets of γδT cells contain one or more chimeric antigen receptors. In some aspects, the chimeric antigen receptors contain one or more antigen-binding domains that are specific for binding to TROP2 and / or PD-L1. In some aspects, the multiple subsets of γδT cells express IL-15. In some aspects, the multiple subsets of γδT cells contain one or more genomic modifications. In some aspects, the multiple subsets of γδT cells contain TGFβR2 knockout. This technology also relates in part to single-domain antibodies (nanoantibodies) targeting TROP2, PD-L1, or both TROP2 and PD-L1, their applications in immune cell engineering, their pharmaceutical compositions, their diagnostic and non-diagnostic reagents, and their therapeutic and non-therapeutic uses. Abstract

Claims

What is claimed is:1 . A modified gamma delta T cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises a first antigen binding domain with binding specificity to TROP2 and a second antigen binding domain with binding specificity to PD-L1 .

2. The modified gamma delta T cell of claim 1 , wherein the first antigen binding domain comprises a variable heavy domain of heavy chain (VHH) or a single-chain variable fragment (ScFv).

3. The modified gamma delta T cell of claim 2, wherein the VHH comprises a hypervariable region H1 (HVR-H1 ) polypeptide, a hypervariable region H2 (HVR-H2) polypeptide, and a hypervariable region H3 (HVR-H3) polypeptide, wherein: a) the HVR-H1 polypeptide is chosen from SEQ ID NO: 18, SEQ ID NO: 70, SEQ ID NO: 46, SEQ ID NO: 14, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 42, SEQ ID NO: 50, SEQ ID NO: 54, SEQ ID NO: 58, SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 74, SEQ ID NO: 78, SEQ ID NO: 82, SEQ ID NO: 86, and SEQ ID NO: 90; b) the HVR-H2 polypeptide is chosen from SEQ ID NO: 19, SEQ ID NO: 71 , SEQ ID NO: 47, SEQ ID NO: 15, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31 , SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 51 , SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 67, SEQ ID NO: 75, SEQ ID NO: 79, SEQ ID NO: 83, SEQ ID NO: 87, and SEQ ID NO: 91 ; and c) the HVR-H3 polypeptide is chosen from SEQ ID NO: 20, SEQ ID NO: 72, SEQ ID NO: 48, SEQ ID NO: 16, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO: 60, SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 76, SEQ ID NO: 80, SEQ ID NO: 83, SEQ ID NO: 88, and SEQ ID NO: 92.

4. The modified gamma delta T cell of claim 2 or 3, wherein the VHH comprises a polypeptide that is about 90% or more identical to a polypeptide chosen from SEQ ID NO: 17, SEQ ID NO: 69, SEQ ID NO: 45, SEQ ID NO: 13, SEQ ID NO: 21 , SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41 , SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61 , SEQ ID NO: 65, SEQ ID NO: 73, SEQ ID NO: 77, SEQ ID NO: 81 , SEQ ID NO: 85, and SEQ ID NO: 89.

5. The modified gamma delta T cell of claim 2 or 3, wherein the VHH comprises a polypeptide that is about 95% or more identical to a polypeptide chosen from SEQ ID NO: 17, SEQ ID NO: 69, SEQ ID NO: 45, SEQ ID NO: 13, SEQ ID NO: 21 , SEQ ID NO: 25, SEQ ID NO: 29, SEQ IDNO: 33, SEQ ID NO: 37, SEQ ID NO: 41 , SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61 , SEQ ID NO: 65, SEQ ID NO: 73, SEQ ID NO: 77, SEQ ID NO: 81 , SEQ ID NO: 85, and SEQ ID NO: 89.

6. The modified gamma delta T cell of claim 2 or 3, wherein the VHH comprises a polypeptide chosen from SEQ ID NO: 17, SEQ ID NO: 69, SEQ ID NO: 45, SEQ ID NO: 13, SEQ ID NO: 21 , SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41 , SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61 , SEQ ID NO: 65, SEQ ID NO: 73, SEQ ID NO: 77, SEQ ID NO: 81 , SEQ ID NO: 85, and SEQ ID NO: 89.

7. The modified gamma delta T cell of claim 2, wherein the ScFv comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain, wherein the VH domain comprises a hypervariable region H1 (HVR-H1 ) polypeptide, a hypervariable region H2 (HVR-H2) polypeptide, and a hypervariable region H3 (HVR-H3) polypeptide, wherein the HVR-H1 comprises the polypeptide of SEQ ID NO: 94, the HVR-H2 comprises the polypeptide of SEQ ID NO: 95, and the HVR-H3 comprises the polypeptide of SEQ ID NO: 96; and the VL domain comprises a hypervariable region L1 (HVR-L1 ) polypeptide, a hypervariable region L2 (HVR-L2) polypeptide, and a hypervariable region L3 (HVR-L3) polypeptide, wherein the HVR-L1 comprises the polypeptide of SEQ ID NO: 98, the HVR-L2 comprises the polypeptide of SEQ ID NO: 99, and the HVR-L3 comprises the polypeptide of SEQ ID NO: 100.

8. The modified gamma delta T cell of claim 7, wherein the VH domain comprises the polypeptide of SEQ ID NO: 93 and the VL comprises the polypeptide of SEQ ID NO: 97.

9. The modified gamma delta T cell of any one of claims 1-8, wherein the second antigen binding domain comprises a VHH comprising a hypervariable region H1 (HVR-H1 ) polypeptide, a hypervariable region H2 (HVR-H2) polypeptide, and a hypervariable region H3 (HVR-H3) polypeptide, wherein: a) the HVR-H1 polypeptide is chosen from SEQ ID NO: 2, SEQ ID NO: 6, and SEQ ID NO: 10; b) the HVR-H1 polypeptide is chosen from SEQ ID NO: 3, SEQ ID NO: 7, and SEQ ID NO: 11 ; and c) a hypervariable region H3 (HVR-H3) polypeptide chosen from SEQ ID NO: 4, SEQ ID NO: 8, and SEQ ID NO: 12.

10. The modified gamma delta T cell of claim 9, wherein the VHH comprises a polypeptide that is about 90% or more identical to a polypeptide chosen from SEQ ID NO: 1 , SEQ ID NO: 5, and SEQ ID NO: 9.11 . The modified gamma delta T cell of claim 9, wherein the VHH comprises a polypeptide that is about 95% or more identical to a polypeptide chosen from SEQ ID NO: 1 , SEQ ID NO: 5, and SEQ ID NO: 9.

12. The modified gamma delta T cell of claim 9, wherein the VHH comprises a polypeptide chosen from SEQ ID NO: 1 , SEQ ID NO: 5, and SEQ ID NO:

913. The modified gamma delta T cell of any one of claims 1 -6 and 9-12, wherein the CAR comprises a polypeptide that is about 90% or more identical to a polypeptide chosen from SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

14. The modified gamma delta T cell of any one of claims 1 -6 and 9-12, wherein the CAR comprises a polypeptide that is about 95% or more identical to a polypeptide chosen from SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

15. The modified gamma delta T cell of any one of claims 1 -6 and 9-12, wherein the CAR comprises a polypeptide chosen from SEQ ID NO: 102, SEQ ID NO: 104, SEQ ID NO: 103, SEQ ID NO: 105, SEQ ID NO: 106, and SEQ ID NO: 107.

16. The modified gamma delta T cell of any one of claims 1 -15, wherein the CAR further comprises an IL-15 component.

17. The modified gamma delta T cell claim 16, wherein the IL-15 component comprises a polypeptide that is about 90% or more identical to the polypeptide of SEQ ID NO: 131 .

18. The modified gamma delta T cell claim 16, wherein the IL-15 component comprises the polypeptide of SEQ ID NO: 131.

19. The modified gamma delta T cell of any one of claims 1 -18, further comprising a genome modification.

20. The modified gamma delta T cell of claim 19, wherein the genome modification is a disrupted gene encoding TGF-beta 2 receptor.