IP Library › Granted Patent US 12,698,328
Granted Patent B2
US 12,698,328 · App. 17/801,786 · Granted Aug 4, 2026

Antibodies

Inventors: Oxana Polyakova (London, GB); Oliver Nussbaumer (London, GB); Adrian Hayday (London, GB); Pierre Vantourout (London, GB)
Assignee: GammaDelta Therapeutics Limited
C07K16/2809A61P35/00C12N5/0634A61K2039/505C07K2317/21C07K2317/34C07K2317/565C07K2317/622C07K2317/74C07K2317/92C12N2501/23
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,698,328
App. No.
17/801,786
Filed
Aug 23, 2022
Granted
Aug 4, 2026
Kind
B2
Art Unit
1645
USPC
424/133.1
Abstract

An isolated antibody or fragment thereof, which specifically binds to a gamma variable 4 (Vγ4) chain of a γδ T cell receptor (TCR) and not to a gamma variable 2 (Vγ2) chain of a γδ TCR is provided herein. Methods of treatment and other uses of said antibodies are also provided along with methods of producing said antibodies.

Claims (110)

1 . An isolated anti-gamma variable 4 (anti-Vγ4) antibody or fragment thereof comprising:

(a) a heavy chain variable (VH) amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 79, a heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 56 and a heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; and

a light chain variable (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 102, a light chain complementarity determining region 2 (LCDR2) of EVT and a light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 33;

(b) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 86, a HCDR2 of SEQ ID NO: 63 and a HCDR3 of SEQ ID NO: 17; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 109, a LCDR2 of QDS and a LCDR3 of SEQ ID NO: 40;

(c) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 73, a HCDR2 of SEQ ID NO: 50 and a HCDR3 of SEQ ID NO: 4; and

a VL comprising a LCDR1 of SEQ ID NO: 96, a LCDR2 of DAS and a LCDR3 of SEQ ID NO: 27;

(d) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 83, a HCDR2 of SEQ ID NO: 60 and a HCDR3 of SEQ ID NO: 14; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 106, a LCDR2 of EIT and a LCDR3 of SEQ ID NO: 37;

(e) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 84, a HCDR2 of SEQ ID NO: 61 and a HCDR3 of SEQ ID NO: 15; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 107, a LCDR2 of RDS and a LCDR3 of SEQ ID NO: 38;

(f) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 88, a HCDR2 of SEQ ID NO: 65 and a HCDR3 of SEQ ID NO: 19; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 111, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 42;

(g) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 92, a HCDR2 of SEQ ID NO: 69 and a HCDR3 of SEQ ID NO: 23; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 115, a LCDR2 of GKN and a LCDR3 of SEQ ID NO: 46;

(h) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 71, a HCDR2 of SEQ ID NO: 48 and a HCDR3 of SEQ ID NO: 2; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 94, a LCDR2 of DAS and a LCDR3 of SEQ ID NO: 25;

(i) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 72, a HCDR2 of SEQ ID NO: 49 and a HCDR3 of SEQ ID NO: 3; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 95, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 26;

(j) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 74, a HCDR2 of SEQ ID NO: 51 and a HCDR3 of SEQ ID NO: 5; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 97, a LCDR2 of WAS and a LCDR3 of SEQ ID NO: 28;

(k) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 75, a HCDR2 of SEQ ID NO: 52 and a HCDR3 of SEQ ID NO: 6; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 98, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 29;

(l) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 76, a HCDR2 of SEQ ID NO: 53 and a HCDR3 of SEQ ID NO: 7; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 99, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 30;

(m) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 77, a HCDR2 of SEQ ID NO: 54 and a HCDR3 of SEQ ID NO: 8; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 100, a LCDR2 of LGS and a LCDR3 of SEQ ID NO: 31;

(n) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 78, a HCDR2 of SEQ ID NO: 55 and a HCDR3 of SEQ ID NO: 9; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 101, a LCDR2 of KVS and a LCDR3 of SEQ ID NO: 32;

(o) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 80, a HCDR2 of SEQ ID NO: 57 and a HCDR3 of SEQ ID NO: 11; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 103, a LCDR2 of EDN and a LCDR3 of SEQ ID NO: 34;

(p) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 81, a HCDR2 of SEQ ID NO: 58 and a HCDR3 of SEQ ID NO: 12; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 104, a LCDR2 of RDK and a LCDR3 of SEQ ID NO: 35;

(q) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 82, a HCDR2 of SEQ ID NO: 59 and a HCDR3 of SEQ ID NO: 13; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 105, a LCDR2 of DVS and a LCDR3 of SEQ ID NO: 36;

(r) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 85, a HCDR2 of SEQ ID NO: 62 and a HCDR3 of SEQ ID NO: 16; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 108, a LCDR2 of DDD and a LCDR3 of SEQ ID NO: 39;

(s) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 87, a HCDR2 of SEQ ID NO: 64 and a HCDR3 of SEQ ID NO: 18; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 110, a LCDR2 of AAS and a LCDR3 of SEQ ID NO: 41;

(t) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 89, a HCDR2 of SEQ ID NO: 66 and a HCDR3 of SEQ ID NO: 20; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 112, a LCDR2 of WAS and a LCDR3 of SEQ ID NO: 43;

(u) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 90, a HCDR2 of SEQ ID NO: 67 and a HCDR3 of SEQ ID NO: 21; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 113, a LCDR2 of EVS and a LCDR3 of SEQ ID NO: 44;

(v) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 91, a HCDR2 of SEQ ID NO: 68 and a HCDR3 of SEQ ID NO: 22; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 114, a LCDR2 of EVS and a LCDR3 of SEQ ID NO: 45;

or

(w) a VH amino acid sequence comprising a HCDR1 of SEQ ID NO: 93, a HCDR2 of SEQ ID NO: 70 and a HCDR3 of SEQ ID NO: 24; and

a VL amino acid sequence comprising a LCDR1 of SEQ ID NO: 116, a LCDR2 of GKN and a LCDR3 of SEQ ID NO: 47.

2 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising an amino acid sequence of any one of SEQ ID NOs: 163-185.

3 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising an amino acid sequence of any one of SEQ ID NOs: 233-255.

4 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising a heavy chain amino acid sequence of any one of SEQ ID NOs: 284-306 and a light chain amino acid sequence of any one of SEQ ID NOs: 307-329.

5 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 , wherein the isolated anti-Vγ4 antibody or fragment thereof is:

(i) an scFv or a full length antibody; and/or

(ii) a human antibody or fragment thereof.

6 . A polynucleotide sequence encoding the anti-Vγ4 antibody or fragment thereof of claim 1 .

7 . An expression vector comprising the polynucleotide sequence of claim 6 .

8 . A cell comprising the polynucleotide sequence of claim 6 .

9 . A composition comprising the antibody or fragment thereof of claim 1 .

10 . A pharmaceutical composition comprising the antibody or fragment thereof of claim 1 and a pharmaceutically acceptable diluent or carrier.

11 . A kit comprising an anti-Vγ4 antibody or fragment thereof of claim 1 .

12 . The isolated anti-Vγ4 antibody or fragment thereof of claim 1 comprising:

(a) a VH comprising an amino acid sequence of SEQ ID NO: 125; and

a VL comprising an amino acid sequence of SEQ ID NO: 148 or 269;

(b) a VH comprising an amino acid sequence of SEQ ID NO: 132; and

a VL comprising an amino acid sequence of SEQ ID NO: 155 or 276;

(c) a VH comprising an amino acid sequence of SEQ ID NO: 119; and

a VL comprising an amino acid sequence of SEQ ID NO: 142 or 263;

(d) a VH comprising an amino acid sequence of SEQ ID NO: 129; and

a VL comprising an amino acid sequence of SEQ ID NO: 152 or 273;

(e) a VH comprising an amino acid sequence of SEQ ID NO: 130; and

a VL comprising an amino acid sequence of SEQ ID NO: 153 or 274;

(f) a VH comprising an amino acid sequence of SEQ ID NO: 134; and

a VL comprising an amino acid sequence of SEQ ID NO: 157 or 278;

(g) a VH comprising an amino acid sequence of SEQ ID NO: 138; and

a VL comprising an amino acid sequence of SEQ ID NO: 161 or 282;

(h) a VH comprising an amino acid sequence of SEQ ID NO: 117; and

a VL comprising an amino acid sequence of SEQ ID NO: 140 or 261;

(i) a VH comprising an amino acid sequence of SEQ ID NO: 118; and

a VL comprising an amino acid sequence of SEQ ID NO: 141 or 262;

(j) a VH comprising an amino acid sequence of SEQ ID NO: 120; and

a VL comprising an amino acid sequence of SEQ ID NO: 143 or 264;

(k) a VH comprising an amino acid sequence of SEQ ID NO: 121; and

a VL comprising an amino acid sequence of SEQ ID NO: 144 or 265;

(l) a VH comprising an amino acid sequence of SEQ ID NO: 122; and

a VL comprising an amino acid sequence of SEQ ID NO: 145 or 266;

(m) a VH comprising an amino acid sequence of SEQ ID NO: 123; and

a VL comprising an amino acid sequence of SEQ ID NO: 146 or 267;

(n) a VH comprising an amino acid sequence of SEQ ID NO: 124; and

a VL comprising an amino acid sequence of SEQ ID NO: 147 or 268;

(o) a VH comprising an amino acid sequence of SEQ ID NO: 126; and

a VL comprising an amino acid sequence of SEQ ID NO: 149 or 270;

(p) a VH comprising an amino acid sequence of SEQ ID NO: 127; and

a VL comprising an amino acid sequence of SEQ ID NO: 150 or 271;

(q) a VH comprising an amino acid sequence of SEQ ID NO: 128; and

a VL comprising an amino acid sequence of SEQ ID NO: 151 or 272;

(r) a VH comprising an amino acid sequence of SEQ ID NO: 131; and

a VL comprising an amino acid sequence of SEQ ID NO: 154 or 275;

(s) a VH comprising an amino acid sequence of SEQ ID NO: 133; and

a VL comprising an amino acid sequence of SEQ ID NO: 156 or 277;

(t) a VH comprising an amino acid sequence of SEQ ID NO: 135; and

a VL comprising an amino acid sequence of SEQ ID NO: 158 or 279;

(u) a VH comprising an amino acid sequence of SEQ ID NO: 136; and

a VL comprising an amino acid sequence of SEQ ID NO: 159 or 280;

(v) a VH comprising an amino acid sequence of SEQ ID NO: 137; and

a VL comprising an amino acid sequence of SEQ ID NO: 160 or 281; or

(w) a VH comprising an amino acid sequence of SEQ ID NO: 139; and

a VL comprising an amino acid sequence of SEQ ID NO: 162 or 283.

13 . A method of expanding a Vγ4+ T cell, the method comprising contacting the Vγ4+ T cell with the isolated anti-Vγ4 antibody or fragment thereof of claim 1 .

14 . A method of detecting a Vγ4+ T cell, the method comprising contacting a sample comprising the Vγ4+ T cell with the isolated anti-Vγ4 antibody or fragment thereof of claim 1 .

15 . A method of treating a cancer, an infectious disease or an inflammatory disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of the isolated anti-Vγ4 antibody or fragment thereof of claim 1 to the subject.

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: ADAPTATE BIOTHERAPEUTICS LIMITED
To: GAMMADELTA THERAPEUTICS LIMITED
Reel/Frame 075266/0883 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: KING'S COLLEGE LONDON
To: GAMMADELTA THERAPEUTICS LIMITED
Reel/Frame 075266/0908 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: POLYAKOVA, OXANA
To: ADAPTATE BIOTHERAPEUTICS LIMITED
Reel/Frame 074142/0394 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: NUSSBAUMER, OLIVER
To: GAMMADELTA THERAPEUTICS LIMITED
Reel/Frame 075170/0309 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 20, 2026
From: HAYDAY, ADRIAN; VANTOUROUT, PIERRE
To: KING'S COLLEGE LONDON
Reel/Frame 075170/0319 →
Priority Claims (1)
GB 2002581 · Feb 24, 2020 · national
Continuity (1)
Related Publication 20230090901A1 · Mar 23, 2023
References Cited (149)
US 9334331B2 · Igawa et al. · 2016 [cited by applicant]
US 10421807B2 · Gonzales et al. · 2019 [cited by applicant]
US 11629193B2 · Tuna et al. · 2023 [cited by applicant]
US 12312408B2 · Tuna et al. · 2025 [cited by applicant]
US 20180228566A9 · McAfee · 2018 [cited by applicant]
US 20190119634A1 · Jakobovits et al. · 2019 [cited by applicant]
US 20220403025A1 · Mount et al. · 2022 [cited by applicant]
US 20230028110A1 · Tuna et al. · 2023 [cited by applicant]
US 20240132599A1 · Tuna et al. · 2024 [cited by applicant]
US 20240376215A1 · Tuna et al. · 2024 [cited by applicant]
CN 101031641A · 2007 [cited by applicant]
CN 109414480A · 2019 [cited by applicant]
JP 2018532383A · 2018 [cited by applicant]
JP 2019519210A · 2019 [cited by applicant]
WO WO03080672A1 · 2003 [cited by applicant]
WO WO2016166544A1 · 2016 [cited by applicant]
WO WO2016198480A1 · 2016 [cited by applicant]
WO WO2017037707A1 · 2017 [cited by applicant]
WO WO2017197347A1 · 2017 [cited by applicant]
WO WO2019005637A2 · 2019 [cited by applicant]
WO WO2019147735A1 · 2019 [cited by applicant]
WO WO2020060406A1 · 2020 [cited by applicant]
WO WO2020154548A2 · 2020 [cited by applicant]
WO WO2020159368A1 · 2020 [cited by applicant]
WO WO2020210232A1 · 2020 [cited by applicant]
WO WO2021032951A1 · 2021 [cited by applicant]
WO WO2021032960A1 · 2021 [cited by applicant]
WO WO2021032961A1 · 2021 [cited by applicant]
WO WO2021032963A1 · 2021 [cited by applicant]
WO WO2022175413A1 · 2022 [cited by applicant]
WO WO2022175414A1 · 2022 [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/GB2020/051959, mailed Mar. 3, 2022. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/GB2020/051959, mailed Oct. 30, 2020. [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/EP2022/054011, mailed May 30, 2022. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/EP2022/054011, mailed Aug. 31, 2023. [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/EP2022/054004, mailed May 24, 2022. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/EP2022/054004, mailed Aug. 31, 2023. [cited by applicant]
Almagro et al., Progress and Challenges in the Design and Clinical Development of Antibodies for Cancer Therapy. Front Immunol. Jan. 4, 2018:8:1751. doi: 10.3389/fimmu.2017.01751. eCollection 2017. [cited by applicant]
Almeida et al., Delta One T Cells for Immunotherapy of Chronic Lymphocytic Leukemia: Clinical-Grade Expansion/Differentiation and Preclinical Proof of Concept. Clin Cancer Res. Dec. 1, 2016;22(23):5795-5804. doi: 10.115… [cited by applicant]
Brown et al., Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation? J Immunol. May 1, 1996;156(9):3285-91. [cited by applicant]
Chitadze et al., The Ambiguous Role of γδ T Lymphocytes in Antitumor Immunity. Trends Immunol. Sep. 2017;38(9):668-678. doi: 10.1016/j.it.2017.06.004. Epub Jul. 11, 2017. [cited by applicant]
Chiu et al., Antibody Structure and Function: The Basis for Engineering Therapeutics. Antibodies (Basel). Dec. 3, 2019;8(4):55. doi: 10.3390/antib8040055. [cited by applicant]
Cordova et al., Characterization of human γδ T lymphocytes infiltrating primary malignant melanomas. Plos One. 2012;7(11):e49878. doi: 10.1371/journal.pone.0049878. Epub Nov. 26, 2012. [cited by applicant]
Davey et al., Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance. Nat Commun. Mar. 1, 2017;8:14760. doi: 10.1038/ncomms14760. [cited by applicant]
De Bruin et al., A bispecific nanobody approach to leverage the potent and widely applicable tumor cytolytic capacity of Vγ9Vδ2-T cells. Oncoimmunology. Oct. 20, 2017;7(1):e1375641. doi: 10.1080/2162402X.2017.1375641. e… [cited by applicant]
De Weerdt et al., A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia. Clin Cancer Res. Mar. 15, 2021;27(6):1744-1755. doi: 10.1158/1078-0432.CCR-20-… [cited by applicant]
Deniger et al., Clinical applications of gamma delta T cells with multivalent immunity. Front Immunol. Dec. 11, 2014;5:636. doi: 10.3389/fimmu.2014.00636. eCollection 2014. [cited by applicant]
Di Lorenzo et al., Broad Cytotoxic Targeting of Acute Myeloid Leukemia by Polyclonal Delta One T Cells. Cancer Immunol Res. Apr. 2019;7(4):552-558. doi: 10.1158/2326-6066.CIR-18-0647. Epub Mar. 20, 2019. [cited by applicant]
Dondelinger et al., Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition. Front Immunol. Oct. 16, 2018:9:2278. doi: 10.3389/fimmu.2018.02278. eCollection 2… [cited by applicant]
Dutta et al., Apoptosis Induced via Gamma Delta T Cell Antigen Receptor “Blocking” Antibodies: A Cautionary Tale. Front Immunol. Jun. 30, 2017:8:776. doi: 10.3389/fimmu.2017.00776. eCollection 2017. [cited by applicant]
Ferrarini et al., Killing of laminin receptor-positive human lung cancers by tumor-infiltrating lymphocytes bearing γδ+ T-cell receptors. J Natl Cancer Inst. Apr. 3, 1996;88(7):436-41. doi: 10.1093/jnci/88.7.436. [cited by applicant]
Fisher et al., Engineering Approaches in Human Gamma Delta T Cells for Cancer Immunotherapy. Front Immunol. Jun. 26, 2018;9:1409. doi: 10.3389/fimmu.2018.01409. eCollection 2018. [cited by applicant]
Fisher et al., Neuroblastoma killing properties of Vδ2 and Vδ2-negative γδT cells following expansion by artificial antigen-presenting cells. Clin Cancer Res. Nov. 15, 2014;20(22):5720-32. doi: 10.1158/1078-0432.CCR-13-… [cited by applicant]
Garber, γδ T cells bring unconventional cancer-targeting to the clinic—again. Nat Biotechnol. Apr. 2020;38(4):389-391. doi: 10.1038/s41587-020-0487-2. [cited by applicant]
Groh et al., Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A. Jun. 8, 1999;96(12):6879-84. doi: 10.1073/pnas.96.12.6879. [cited by applicant]
Jefferis et al., Human immunoglobulin allotypes: possible implications for immunogenicity. Mabs. Jul.-Aug. 2009;1(4):332-8. doi: 10.4161/mabs.1.4.9122. [cited by applicant]
Kitayama et al., Functional analysis of TCR gamma delta+ T cells in tumour-infiltrating lymphocytes (TIL) of human pancreatic cancer. Clin Exp Immunol. Sep. 1993;93(3):442-7. doi: 10.1111/j.1365-2249.1993.tb08198.x. [cited by applicant]
Knight et al., Human Vdeltal gamma-delta T cells exert potent specific cytotoxicity against primary multiple myeloma cells. Cytotherapy. Oct. 2012;14(9):1110-8. doi: 10.3109/14653249.2012.700766. Epub Jul. 17, 2012. [cited by applicant]
Luoma et al., Crystal structure of Vδ1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells. Immunity. Dec. 12, 2013;39(6):1032-42. doi: 10.1016/j.immuni.2013.11.… [cited by applicant]
Maeurer et al., Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin. J Exp Med. Apr. 1, 1996;183(4):1681-96. doi: 10.1084/jem.183.4.1681. [cited by applicant]
Mahvi et al., Overexpression of 27-kDa heat-shock protein in MCF-7 breast cancer cells: effects on lymphocyte-mediated killing by natural killer and gamma delta T cells. Cancer Immunol Immunother. Aug. 1993;37(3):181-6.… [cited by applicant]
Mikulak et al., NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer. JCI Insight. Dec. 19, 2019;4(24):e125884. doi: 10.1172/jci.insight… [cited by applicant]
Oberg et al., Bispecific antibodies enhance tumor-infiltrating T cell cytotoxicity against autologous HER-2-expressing high-grade ovarian tumors. J Leukoc Biol. Jun. 2020;107(6):1081-1095. doi: 10.1002/JLB.5MA1119-265R.… [cited by applicant]
Oberg et al., Novel bispecific antibodies increase γδ T-cell cytotoxicity against pancreatic cancer cells. Cancer Res. Mar. 1, 2014;74(5):1349-60. doi: 10.1158/0008-5472.CAN-13-0675. Epub Jan. 21, 2014. [cited by applicant]
Romagné et al., Structural analysis of γδ TCR using a novel set of TCR γ and δ chain-specific monoclonal antibodies generated against soluble γδ TCR: Evidence for a specific conformation adopted by the Jδ2 region and fo… [cited by applicant]
Rudikoff et al., Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. Mar. 1982;79(6):1979-83. doi: 10.1073/pnas.79.6.1979. [cited by applicant]
Sebestyen et al., Translating gammadelta (γδ) T cells and their receptors into cancer cell therapies. Nat Rev Drug Discov. Mar. 2020;19(3):169-184. doi: 10.1038/s41573-019-0038-z. Epub Sep. 6, 2019. [cited by applicant]
Sela-Culang et al., The structural basis of antibody-antigen recognition. Front Immunol. Oct. 8, 2013:4:302. doi: 10.3389/fimmu.2013.00302. [cited by applicant]
Siegers et al., Cytotoxic and regulatory properties of circulating Vδ1+ γδ T cells: a new player on the cell therapy field? Mol Ther. Aug. 2014;22(8):1416-1422. doi: 10.1038/mt.2014.104. Epub Jun. 4, 2014. [cited by applicant]
Wu et al., Ex vivo expanded human circulating Vδ1 γδT cells exhibit favorable therapeutic potential for colon cancer. OncoImmunology. Jan. 22, 2015;4(3):e992749. doi: 10.4161/2162402X.2014.992749. eCollection Mar. 2015. [cited by applicant]
Xu et al., Crystal structure of a γδ T-cell receptor specific for the human MHC class I homolog MICA. Proc Natl Acad Sci U S A. Feb. 8, 2011;108(6):2414-9. doi: 10.1073/pnas.1015433108. Epub Jan. 24, 2011. [cited by applicant]
Invitation to Pay Additional Fees for Application No. PCT/GB2021/050459, mailed Jun. 7, 2021. [cited by applicant]
International Search Report and Written Opinion for Application No. PCT/GB2021/050459, mailed Jul. 28, 2021. [cited by applicant]
International Preliminary Report on Patentability for Application No. PCT/GB2021/050459, mailed Sep. 9, 2022. [cited by applicant]
Blink et al., γδ T cell subsets play opposing roles in regulating experimental autoimmune encephalomyelitis. Cell Immunol. Jul. 2014;290(1):39-51. doi: 10.1016/j.cellimm.2014.04.013. Epub May 10, 2014. Author Manuscript… [cited by applicant]
Davodeau et al., Surface expression of two distinct functional antigen receptors on human gamma delta T cells. Science. Jun. 18, 1993;260(5115):1800-2. doi: 10.1126/science.8390096. [cited by applicant]
De Libero et al., Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells. J Exp Med. Jun. 1, 1991;173(6):1311-22. doi: 10.1084/jem.173.6.1311. [cited by applicant]
Khairallah et al., γδ T cells confer protection against murine cytomegalovirus (MCMV) PLoS Pathog. Mar. 6, 2015;11(3):e1004702. doi: 10.1371/journal.ppat.1004702. eCollection Mar. 2015. [cited by applicant]
Langerak et al., Immunophenotypic and immunogenotypic characteristics of TCRgammadelta+ T cell acute lymphoblastic leukemia. Leukemia. Feb. 1999;13(2):206-14. doi: 10.1038/sj.leu.2401276. [cited by applicant]
No Author Listed, Purified anti-mouse TCR V[gamma]4 Antibody Antigen. Biolegend. Version 1. Last revised: Aug. 10, 2020. Retrieved from the Internet: URL: https://www.biolegend.com/en-ie/global-elements/pdg-popup/purifi… [cited by applicant]
Abeler-Dörner et al., Butyrophilins: an emerging family of immune regulators. Trends Immunol. Jan. 2012;33(1):34-41. doi: 10.1016/j.it.2011.09.007. Epub Oct. 24, 2011. [cited by applicant]
Mayassi et al., Chronic Inflammation Permanently Reshapes Tissue-Resident Immunity in Celiac Disease. Cell. Feb. 21, 2019;176(5):967-981.e19. doi: 10.1016/j.cell.2018.12.039. Epub Feb. 7, 2019. [cited by applicant]
Yamashiro et al., Stimulation of human butyrophilin 3 molecules results in negative regulation of cellular immunity. J Leukoc Biol. Oct. 2010;88(4):757-67. doi: 10.1189/jlb.0309156. Epub Jul. 7, 2010. [cited by applicant]
Al Qaraghuli et al., Antibody-protein binding and conformational changes: identifying allosteric signalling pathways to engineer a better effector response. Sci Rep. 2020; 10: 13696. Published online Aug. 13, 2020. doi:… [cited by applicant]
An et al., IgG2m4, an engineered antibody isotype with reduced Fc function. MAbs. Nov.-Dec. 2009;1(6):572-9. doi: 10.4161/mabs.1.6.10185. [cited by applicant]
Aruda et al., Impact of gd T cells on clinical outcome of hematopoietic stem cell transplantation: systematic review and meta-analysis. Blood Adv. 2019; 3 (21): 3436-3448. https://doi.org/10.1182/bloodadvances.201900068… [cited by applicant]
Bruhns et al., Specificity and affinity of human Fcgamma receptors and their polymorphic variants for human IgG subclasses. Blood. Apr. 16, 2009;113(16):3716-25. doi: 10.1182/blood-2008-09-179754. Epub Nov. 18, 2008. [cited by applicant]
Catellani et al., Expansion of Vdelta1 T lymphocytes producing IL-4 in low-grade non-Hodgkin lymphomas expressing UL-16-binding proteins. Blood. Mar. 1, 2007;109(5):2078-85. doi: 10.1182/blood-2006-06-028985. Epub Sep. … [cited by applicant]
Chen et al., Distribution and functions of γδ T cells infiltrated in the ovarian cancer microenvironment. J Transl Med. May 7, 2019;17(1):144. doi: 10.1186/s12967-019-1897-0. [cited by applicant]
Chothia et al., Conformations of immunoglobulin hypervariable regions. Nature. Dec. 1989;342(6252):877-83. doi: 10.1038/342877a0. [cited by applicant]
Crescioli et al., IgG4 Characteristics and Functions in Cancer Immunity. Curr Allergy Asthma Rep. Jan. 2016;16(1):7. doi: 10.1007/s11882-015-0580-7. [cited by applicant]
Dahlén et al., Bispecific antibodies in cancer immunotherapy. Ther Adv Vaccines Immunother. Feb. 2018;6(1):3-17. doi: 10.1177/2515135518763280. Epub Mar. 28, 2018. [cited by applicant]
Daley et al., γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation. Cell. Sep. 8, 2016;166(6):1485-1499.e15. doi: 10.1016/j.cell.2016.07.046. Epub Aug. 25, 2016. [cited by applicant]
Declaration and Curriculum Vitae of Professor Frits Koning. Signed Mar. 11, 2025. 48 pages. [cited by applicant]
Deniger et al., Activating and propagating polyclonal gamma delta T cells with broad specificity for malignancies. Clin Cancer Res. Nov. 15, 2014;20(22):5708-19. doi: 10.1158/1078-0432.CCR-13-3451. Epub May 15, 2014. [cited by applicant]
Dopfer et al., The CD3 conformational change in the γδ T cell receptor is not triggered by antigens but can be enforced to enhance tumor killing. Cell Rep. Jun. 12, 2014;7(5):1704-1715. doi: 10.1016/j.celrep.2014.04.049… [cited by applicant]
Edwards et al., The remarkable flexibility of the human antibody repertoire; isolation of over one thousand different antibodies to a single protein, BLyS. J Mol Biol. Nov. 14, 2003;334(1):103-18. doi: 10.1016/j.jmb.200… [cited by applicant]
Einsele et al., The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer. Jul. 15, 2020;126(14):3192-3201. doi: 10.1002/cncr.32909.… [cited by applicant]
Gaspar et al., CD137/OX40 Bispecific Antibody Induces Potent Antitumor Activity that Is Dependent on Target Coengagement. Cancer Immunol Res. Jun. 2020;8(6):781-793. doi: 10.1158/2326-6066.CIR-19-0798. Epub Apr. 9, 2020. [cited by applicant]
Gentles et al., The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. Author manuscript; available in PMC May 2, 2016. Published in final edited form as: Nat Med. Aug. 2015; 21(8… [cited by applicant]
Godder et al., Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation. Bone Marrow Transplant. Jun. 2… [cited by applicant]
Goel et al., Plasticity within the antigen-combining site may manifest as molecular mimicry in the humoral immune response. J Immunol. Dec. 15, 2004;173(12):7358-67. doi: 10.4049/jimmunol.173.12.7358. [cited by applicant]
Gonzales et al., Minimizing the Immunogenicity of Antibodies for Clinical Application. Tumour Biol. Jan.-Feb. 2005;26(1):31-43. doi: 10.1159/000084184. [cited by applicant]
He et al., Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin. J Immunol. Jul. 1, 2010;185(1):126-33. doi: 10.4049/jimmunol.0903767. Epub Jun. 4… [cited by applicant]
Herrman et al., Bifunctional PD-1×αCD3×αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia. Blood. Dec. 6, 2018;132(23):2484-2494. doi: 10.1182/blood-2018-05-849802. Epub Oct. 1, 2018. [cited by applicant]
Kabat et al., Sequences of Proteins of Immunological Interest. vol. 1. Fifth Edition. U.S. Department of Health and Human Services. National Institutes of Health. 1991. NIH Publication No. 91-3242. [cited by applicant]
Khan et al., Adjustable locks and flexible keys: plasticity of epitope-paratope interactions in germline antibodies. J Immunol. Jun. 1, 2014;192(11):5398-405. doi: 10.4049/jimmunol.1302143. Epub Apr. 30, 2014. [cited by applicant]
Kim et al., Spectrum of EGFR Gene Copy Number Changes and KRAS Gene Mutation Status in Korean Triple Negative Breast Cancer Patients. PLoS One. Oct. 30, 2013;8(10):e79014. doi: 10.1371/journal.pone.0079014. eCollection … [cited by applicant]
Kontermann, Strategies to Extend Plasma Half-Lives of Recombinant Antibodies. BioDrugs. 2009;23(2):93-109. doi: 10.2165/00063030-200923020-00003. [cited by applicant]
Kunik et al., Structural Consensus among Antibodies Defines the Antigen Binding Site. PLoS Comput Biol. 2012;8(2):e1002388. doi: 10.1371/journal.pcbi.1002388. Epub Feb. 23, 2012. [cited by applicant]
Lejeune et al., Bispecific, T-Cell-Recruiting Antibodies in B-Cell Malignancies. Front Immunol. May 7, 2020:11:762. doi: 10.3389/fimmu.2020.00762. eCollection 2020. [cited by applicant]
Li et al., Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing. Cancer Cell. Mar. 13, 2017;31(3):383-395. doi: 10.1016/j.ccell.2017.02… [cited by applicant]
Li et al., The Dual Roles of Human yo T Cells: Anti-Tumor or Tumor-Promoting. Front Immunol. Feb. 16, 2021:11:619954. doi: 10.3389/fimmu.2020.619954. eCollection 2020. [cited by applicant]
Licitra et al., Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carci… [cited by applicant]
Liu et al., The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy. Cells. May 13, 2020;9(5):1206. doi: 10.3390/cells9051206. [cited by applicant]
Liu, Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell. Jan. 2018;9(1):15-32. doi: 10.1007/s13238-017-0408-4. Epub Apr. 19, 2017. [cited by applicant]
Lloyd et al., Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens. Protein Eng Des Sel. Mar. 2009;22(3):159-68. doi: 10.1093/pr… [cited by applicant]
Lucchese et al., How a single amino acid change may alter the immunological information of a peptide. Front Biosci (Elite Ed). Jan. 1, 2012;4(5):1843-52. doi: 10.2741/e506. [cited by applicant]
Lum et al., Targeting T Cells with Bispecific Antibodies for Cancer Therapy. BioDrugs. Author manuscript; available in PMC: Oct. 8, 2013. Published in final edited form as: BioDrugs. Dec. 1, 2011;25(6):365-379. doi: 10.… [cited by applicant]
Ma et al., A novel bispecific nanobody with PD-L1/TIGIT dual immune checkpoint blockade. Biochem Biophys Res Commun. Oct. 15, 2020;531(2):144-151. doi: 10.1016/j.bbrc.2020.07.072. Epub Aug. 8, 2020. [cited by applicant]
Ma et al., IL-17A produced by γδ T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. Apr. 1, 2014;74(7):1969-82. doi: 10.1158/0008-5472.CAN-13-2534. Epub Feb. 13, 2014. [cited by applicant]
Mix et al., Immunoglobulins—Basic considerations. J Neurol. Sep. 2006:253 Suppl 5:V9-17. doi: 10.1007/s00415-006-5002-2. [cited by applicant]
No Author Listed, Certified copy of priority document for Application No. GB1911799.3, filed Aug. 16, 2019. 82 pages. [cited by applicant]
No Author Listed, Certified copy of priority document for Application No. GB2010760.3, filed Jul. 13, 2020. 96 pages. [cited by applicant]
No Author Listed, Certified copy of priority document for Application No. GB2012172.9, filed Aug. 5, 2020. 131 pages. [cited by applicant]
No Author Listed, NCBI Gene ID: 2191; FAP fibroblast activation protein alpha [ [cited by applicant]
No Author Listed, Sequence Listing for WO2021032960. GammaDelta Therapeutics Limited. 99 pages. [cited by applicant]
Oberg et al., Monitoring Circulating γδ T Cells in Cancer Patients to Optimize γδ T Cell-Based Immunotherapy. Front Immunol. Dec. 17, 2014:5:643. doi: 10.3389/fimmu.2014.00643. eCollection 2014. [cited by applicant]
Padlan, Anatomy of the antibody molecule. Mol Immunol. Feb. 1994;31(3):169-217. doi: 10.1016/0161-5890(94)90001-9. [cited by applicant]
Panka et al., Variable region framework differences result in decreased or increased affinity of variant anti-digoxin antibodies. Proc Natl Acad Sci U S A. May 1988;85(9):3080-4. doi: 10.1073/pnas.85.9.3080. [cited by applicant]
Peng et al., Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique toll-like receptor signaling pathway. Immunity. Aug. 2007;27(2):334-48. doi: 10.1016/j.immu… [cited by applicant]
Poccia et al., Anti-severe acute respiratory syndrome coronavirus immune responses: the role played by V gamma 9V delta 2 T cells. J Infect Dis. May 1, 2006;193(9):1244-9. doi: 10.1086/502975. Epub Mar. 27, 2006. [cited by applicant]
Poosarla et al., Computational de novo design of antibodies binding to a peptide with high affinity. Biotechnol Bioeng. Jun. 2017;114(6):1331-1342. doi: 10.1002/bit.26244. Epub Feb. 2, 2017. [cited by applicant]
Qin et al., Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. Nov. 6, 2019;18(1):155. doi: 10.1186/s12943-019-1091-2. [cited by applicant]
Siegers et al., Human Vδ1 γδ T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells. Cytotherapy. Jul. 2011;13(6):753-64. doi: 10.3109/14653249.201… [cited by applicant]
Strohl et al., Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells. Antibodies (Basel). Jul. 3, 2019;8(3):41. doi: 10.3390/antib8030041. [cited by applicant]
Strohl et al., Therapeutic antibody classes. Chapter 9 in: Therapeutic Antibody Engineering: Current and Future Advances Driving the Strongest Growth Area in the Pharmaceutical Industry. 1st edition. Woodhead Publishing… [cited by applicant]
Tamura et al., Structural Correlates of an Anticarcinoma Antibody: Identification of Specificity-Determining Residues (SDRs) and Development of a Minimally Immunogenic Antibody Variant by Retention of SDRs Only. J Immun… [cited by applicant]
Ternant et al., Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins. Expert Opin Biol Ther. Sep. 2005:5 Suppl 1:S37-47. doi: 10.1517/14712598.5.1.s37. [cited by applicant]
Van Dorp et al., Therapeutic Potential of Gammadelta T-Cells in Controlling CMV After Allogeneic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation. 2011; 17(2): S217. [cited by applicant]
Vidarsson et al., IgG subclasses and allotypes: from structure to effector functions. Front Immunol. Oct. 20, 2014:5:520. doi: 10.3389/fimmu.2014.00520. eCollection 2014. [cited by applicant]
Wark et al., Latest technologies for the enhancement of antibody affinityB. Adv Drug Deliv Rev. Aug. 7, 2006;58(5-6):657-70. doi: 10.1016/j.addr.2006.01.025. Epub May 22, 2006. [cited by applicant]
Wu et al., An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer. Sci Transl Med. Oct. 9, 2019;11(513):eaax9364. doi: 10.1126/scitranslmed.aax9364. [cited by applicant]
Wu et al., Humanization of a Murine Monoclonal Antibody by Simultaneous Optimization of Framework and CDR Residues. J Mol Biol. Nov. 19, 1999;294(1):151-62. doi: 10.1006/jmbi.1999.3141. [cited by applicant]
Xenaki et al., Antibody or Antibody Fragments: Implications for Molecular Imaging and Targeted Therapy of Solid Tumors. Front Immunol. Oct. 12, 2017:8:1287. doi: 10.3389/fimmu.2017.01287. eCollection 2017. [cited by applicant]
Xu et al., In vitro characterization of five humanized OKT3 effector function variant antibodies. Cell Immunol. Feb. 25, 2000;200(1):16-26. doi: 10.1006/cimm.2000.1617. [cited by applicant]
Ye et al., Specific recruitment of γδ regulatory T cells in human breast cancer. Cancer Res. Oct. 15, 2013;73(20):6137-48. doi: 10.1158/0008-5472.CAN-13-0348. Epub Aug. 19, 2013. [cited by applicant]
Zhang et al., Epidermal growth factor receptor expression and gene copy number analysis in gastric carcinoma samples from Chinese patients. Oncol Lett. Jan. 2016;11(1):173-181. doi: 10.3892/01.2015.3875. Epub Nov. 5, 20… [cited by applicant]
Zhao et al., Protective Role of γδ T Cells in Different Pathogen Infections and Its Potential Clinical Application. J Immunol Res. Jul. 10, 2018:2018:5081634. doi: 10.1155/2018/5081634. eCollection 2018. [cited by applicant]