US 2025/0051454 A1 · ANTIBODIES THAT TARGET HLA-E-HOST PEPTIDE COMPLEXES AND USES THEREOF

Abstract

Recombinant monoclonal antibodies (mAbs) and fragments that bind specifically to an HLA-E-peptide complex, including HLA-E-VL9 complexes, and regulate the cytotoxicity effector cell function of NK and/or CD8+ T-cells positive for cell-surface expression of NKG2A (“NKG2A+”). Herein, monoclonal antibodies were recombinantly derived from isolated functional HLA-E-VL9-specific mAbs from HLA-E-VL9 peptide-immunized HLA-B transgenic mice and from the naive human B cell repertoire. Such antibodies are capable of regulating effector cell cytotoxicity and can preferentially recognize HLA-E-VL9 peptide complexes expressed on the surface of tumor cells. The invention provides methods for using HLA-E-VL9 m Abs to modulate NK and/or CD8+ T-cell function as part of immunotherapeutic strategies.

Claims40

Dependent claims

1-60. (canceled)

A recombinant antibody or fragment thereof selected from the group consisting of:

3H4, CA147, 13F11, 10C10, 2D6, CA118, CA119, CA120, CA122, CA123, CA124, CA125, CA127, CA128, CA129, CA130, CA131, CA132, CA133, CA134, CA135, CA136, CA137, CA138, CA139, CA140, CA141, CA143, CA144, CA145, CA146, CA401, 3H4 Gv2, 3H4 Gv3, 3H4 Gv4, 3H4 Gv5, 3H4 Gv6, 3H4 Gv7, 3H4 Gv8, 3H4 Gv9, 3H4 Gv10, 3H4 Gv11, 3H4 Gv12, CA147hexa, CA147sortaNP, 3H4hexa, and 3H4sortaNP;
wherein 3H4 comprises a heavy chain variable region (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:
128 and a light chain variable region (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein CA147 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
184 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
185;
wherein 13F11 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
130 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
131;
wherein 10C10 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
132 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
133;
wherein 2D6 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
134 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
135;
wherein CA118 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
136 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
137;
wherein CA119 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
138 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
139;
wherein CA120 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
140 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
141;
wherein CA122 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
142 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
143;
wherein CA123 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
144 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
145;
wherein CA124 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
146 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
147;
wherein CA125 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
148 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
149;
wherein CA127 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
150 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
151;
wherein CA128 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
152 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
153;
wherein CA129 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
154 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
155;
wherein CA130 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
156 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
157;
wherein CA131 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
158 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
159;
wherein CA132 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
156 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
141;
wherein CA133 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
160 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
161;
wherein CA134 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
162 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
163;
wherein CA135 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
164 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
157;
wherein CA136 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
165 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
166;
wherein CA137 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
167 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
157;
wherein CA138 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
168 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
169;
wherein CA139 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
170 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
171;
wherein CA140 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
172 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
173;
wherein CA141 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
174 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
175;
wherein CA143 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
176 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
177;
wherein CA144 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
178 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
179;
wherein CA145 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
180 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
181;
wherein CA146 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
182 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
183;
wherein CA401 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
186 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
187;
wherein 3H4 Gv2 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
35 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv3 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
36 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv4 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
37 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv5 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
38 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv6 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
39 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv7 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
40 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv8 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
41 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv9 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
42 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv10 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
43 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv1 1 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
44 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein 3H4 Gv12 comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
45 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
129;
wherein CA147hexa comprises a VH comprising an amino acid sequence at least 80% identical to all consecutive amino acids after the signal peptide of SEQ ID NO:
340 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
351;
wherein CA147sortaNP comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
349 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
351;
wherein 3H4hexa comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
338 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
345;
and
wherein 3H4sortaNP comprises a VH comprising an amino acid sequence at least 80% identical to SEQ ID NO:
343 and a VL comprising an amino acid sequence at least 80% identical to SEQ ID NO:
345.

140 more elements

A humanized antibody or fragment thereof selected from the group consisting of:

3H4, 13F11, 10C10, 2D6, 3H4 Gv2, 3H4 Gv3, 3H4 Gv4, 3H4 Gv5, 3H4 Gv6, 3H4 Gv7, 3H4 Gv8, 3H4 Gv9, 3H4 Gv10, 3H4 Gv11, 3H4 Gv12, 3H4hexa, and 3H4sortaNP;
wherein 3H4 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
128 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 13F11 comprises VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
130 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
131;
wherein 10C10 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
132 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
133;
wherein 2D6 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
134 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
135;
wherein 3H4 Gv2 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
35 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv3 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
36 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv4 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
37 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv5 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
38 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv6 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
39 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv7 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
40 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv8 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
41 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv9 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
42 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv10 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
43 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv1 1 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
44 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4 Gv12 comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
45 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
129;
wherein 3H4hexa comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
338 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
345;
and
wherein 3H4sortaNP comprises a VH comprising HCDR1, HCDR2 and HCDR3 sequences at least 80% identical to the HCDR1, HCDR2 and HCDR3 sequences of SEQ ID NO:
343 and a VL comprising LCDR1, LCDR2 and LCDR3 sequences at least 80% identical to the LCDR1, LCDR2 and LCDR3 sequences of SEQ ID NO:
345

50 more elements

Dependencies are inferred from the claim text.

Facts

Application

18/245,540Filed 15 Sep 2021

Priority

15 Sep 2020

Published

13 Feb 2025

Term ends

Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07K 14/70539
Immunoglobulin superfamily: mHC-molecules, e.g. HLA-molecules
A61P 35/00
Antineoplastic agents
C07K 16/104
Coronaviridae: severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]
C07K 16/2833
Against the immunoglobulin superfamily: against MHC-molecules, e.g. HLA-molecules

Family

Application63/078,780Us provisional application · filed 15 Sep 2020

Application63/121,031Us provisional application · filed 3 Dec 2020

Application63/121,036Us provisional application · filed 3 Dec 2020

Application63/235,535Us provisional application · filed 20 Aug 2021

US 2025/0051454 A1This patent

From the US filing history. Foreign family members aren’t listed.

Antibodies that target hla-e-host peptide complexes and uses thereof

Life of this patent

Antibodies that target hla-e-host peptide complexes and uses thereof

Life of this patent

Abstract

Claims40