IP Library › Granted Patent US 12,281,172
Granted Patent B2
US 12,281,172 · App. 17/221,627 · Granted Apr 22, 2025

Cross-species-specific PSMAxCD3 bispecific single chain antibody

Inventors: Peter Kufer (Moosburg an der Isar, DE); Tobias Raum (Eurasburg, DE); Roman Kischel (Munich, DE); Ralf Lutterbüse (Neuried, DE); Patrick Hoffmann (Bad Heilbrunn, DE); Doris Rau (Munich, DE); Susanne Mangold (Cham, CH); Matthias Klinger (Gilching, DE); Evelyne Schaller (Munich, DE); Susanne Hausmann (Sauerlach, DE); Petra Fluhr (Dachau, DE); Carola Steiger (Augsburg, DE)
Assignee: AMGEN RESEARCH (MUNICH) GMBH
C07K16/3069A61K2039/505C07K2317/31C07K2317/34
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Quick Facts
Patent No.
US 12,281,172
App. No.
17/221,627
Granted
Apr 22, 2025
Kind
B2
Abstract

The present invention relates to a bispecific single chain antibody molecule comprising a first binding domain capable of binding to an epitope of human and non-chimpanzee primate CD3 epsilon chain, wherein the epitope is part of an amino acid sequence comprised in the group consisting of SEQ ID NOs. 2, 4, 6, and 8, and a second binding domain capable of binding to prostate-specific membrane antigen (PSMA). The invention also provides nucleic acids encoding said bispecific single chain antibody molecule as well as vectors and host cells and a process for its production. The invention further relates to pharmaceutical compositions comprising said bispecific single chain antibody molecule and medical uses of said bispecific single chain antibody molecule.

Claims (67)

1. A bispecific single chain antibody molecule comprising a first binding domain that specifically binds to human CD3 epsilon (CD3ε) chain and a second binding domain that specifically binds to human prostate-specific membrane antigen (PSMA), wherein the first binding domain comprises a light chain variable (VL CD3ε) region comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 and a heavy chain variable (VH CD3ε) region comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, and wherein CDR-L1 has the sequence of SEQ ID NO: 171, CDR-L2 has the sequence of SEQ ID NO: 172, CDR-L3 has the sequence of SEQ ID NO: 173, CDR-H1 has the sequence of SEQ ID NO: 174, CDR-H2 has the sequence of SEQ ID NO: 175, and CDR-H3 has the sequence of SEQ ID NO: 176.

2. The bispecific single chain antibody molecule of claim 1 , wherein at least one of said first and second binding domains is humanized.

3. The bispecific single chain antibody molecule of claim 1 , wherein the VL CD3g region comprises the sequence of SEQ ID NO: 179 and the VH CD3ε region comprises the sequence of SEQ ID NO: 177.

4. The bispecific single chain antibody molecule of claim 1 , wherein the first binding domain comprises the amino acid sequence of SEQ ID NO: 185.

5. The bispecific single chain antibody molecule of claim 1 , wherein the second binding domain comprises a light chain variable (VL PSMA) region comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 and a heavy chain variable (VH PSMA) region comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, wherein:

a) CDR H1-3 comprises the sequences of SEQ ID NO: 394-396, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 389-391, respectively;

b) CDR H1-3 comprises the sequences of SEQ ID NO: 408-410, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 403-405, respectively;

c) CDR H1-3 comprises the sequences of SEQ ID NO: 422-424, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 417-419, respectively;

d) CDR H1-3 comprises the sequences of SEQ ID NO: 436-438, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 431-433, respectively;

e) CDR H1-3 comprises the sequences of SEQ ID NO: 445-447, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 450-452, respectively;

f) CDR H1-3 comprises the sequences of SEQ ID NO: 464-466, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 459-461, respectively;

g) CDR H1-3 comprises the sequences of SEQ ID NO: 478-480, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 473-475, respectively;

h) CDR H1-3 comprises the sequences of SEQ ID NO: 492-494, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 487-489, respectively;

i) CDR H1-3 comprises the sequences of SEQ ID NO: 506-508, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 501-503, respectively;

j) CDR H1-3 comprises the sequences of SEQ ID NO: 520-522, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 515-517, respectively;

k) CDR H1-3 comprises the sequences of SEQ ID NO: 534-536, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 529-531, respectively;

l) CDR H1-3 comprises the sequences of SEQ ID NO: 548-550, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 543-545, respectively;

m) CDR H1-3 comprises the sequences of SEQ ID NO: 562-564, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 557-559, respectively;

n) CDR H1-3 comprises the sequences of SEQ ID NO: 576-578, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 571-573, respectively;

o. CDR H1-3 comprises the sequences of SEQ ID NO: 590-592, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 585-587, respectively;

p) CDR H1-3 comprises the sequences of SEQ ID NO: 604-606, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 599-601, respectively;

q) CDR H1-3 comprises the sequences of SEQ ID NO: 618-620, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 613-615, respectively;

r) CDR H1-3 comprises the sequences of SEQ ID NO: 632-634, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 627-629, respectively;

s) CDR H1-3 comprises the sequences of SEQ ID NO: 646-648, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 641-643, respectively;

t) CDR H1-3 comprises the sequences of SEQ ID NO: 660-662, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 655-657, respectively;

u) CDR H1-3 comprises the sequences of SEQ ID NO: 674-676, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 669-671, respectively;

v) CDR H1-3 comprises the sequences of SEQ ID NO: 688-690, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 683-685, respectively;

w) CDR H1-3 comprises the sequences of SEQ ID NO: 702-704, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 697-699, respectively;

x) CDR H1-3 comprises the sequences of SEQ ID NO: 716-718, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 711-713, respectively;

y) CDR H1-3 comprises the sequences of SEQ ID NO: 729-731, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 724-726, respectively;

z) CDR H1-3 comprises the sequences of SEQ ID NO: 788-790, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 793-795, respectively;

aa) CDR H1-3 comprises the sequences of SEQ ID NO: 806-808, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 811-813, respectively;

ab) CDR H1-3 comprises the sequences of SEQ ID NO: 852-854, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 857-859, respectively;

ac) CDR H1-3 comprises the sequences of SEQ ID NO: 838-840, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 843-845, respectively;

ad) CDR H1-3 comprises the sequences of SEQ ID NO: 824-826, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 829-831, respectively;

ae) CDR H1-3 comprises the sequences of SEQ ID NO: 774-776, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 779-781, respectively;

af) CDR H1-3 comprises the sequences of SEQ ID NO: 688-690, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 683-685, respectively;

ag) CDR H1-3 comprises the sequences of SEQ ID NO: 870-872, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 875-877, respectively;

ah) CDR H1-3 comprises the sequences of SEQ ID NO: 888-890, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 893-895, respectively;

ai) CDR H1-3 comprises the sequences of SEQ ID NO: 924-926, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 929-931, respectively;

aj) CDR H1-3 comprises the sequences of SEQ ID NO: 1019-1021, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 1025-1027, respectively;

ak) CDR H1-3 comprises the sequences of SEQ ID NO: 1006-1008, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 1011-1013, respectively;

al) CDR H1-3 comprises the sequences of SEQ ID NO: 906-908, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 911-913, respectively;

am) CDR H1-3 comprises the sequences of SEQ ID NO: 992-994, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 997-999, respectively;

an) CDR H1-3 comprises the sequences of SEQ ID NO: 942-944, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 947-949, respectively;

ao) CDR H1-3 comprises the sequences of SEQ ID NO: 960-962, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 965-967, respectively; or

ap) CDR H1-3 comprises the sequences of SEQ ID NO:978-980, respectively and CDR L1-3 comprises the sequences of SEQ ID NO: 983-985, respectively.

6. The bispecific single chain antibody molecule of claim 5 , wherein the variable regions in the bispecific single chain antibody molecule are arranged in an amino to carboxyl terminal order of VH PSMA-VL PSMA-VH CD3ε-VL CD3ε or VL PSMA-VH PSMA-VH CD3ε-VL CD3ε.

7. The bispecific single chain antibody molecule of claim 6 , wherein the bispecific single chain antibody molecule comprises a sequence selected from:

(a) an amino acid sequence as depicted in any of SEQ ID NOs: 399, 413, 427, 441, 455, 469, 483, 497, 511, 525, 539, 553, 567, 581, 595, 609, 623, 637, 651, 665, 679, 693, 707, 721, 734, 799, 817, 863, 849, 835, 785, 899, 935, 1017, 1031, 917, 1003, 953, 971 or 989;

(b) an amino acid sequence encoded by a nucleic acid sequence as depicted in any of SEQ ID NOs: 400, 414, 428, 442, 456, 470, 484, 498, 512, 526, 540, 554, 568, 582, 596, 610, 624, 638, 652, 666, 680, 694, 708, 736, 735, 800, 818, 864, 850, 836, 786, 882, 900, 936, 1018, 1032, 918, 1004, 954, 972, 990, 804, 822, 868, 886, 904, 940, 922, 958 or 976; and

(c) an amino acid sequence at least 90% identical or at least 95% identical to the amino acid sequence of (a) or (b).

8. A nucleic acid comprising a nucleotide sequence encoding the bispecific single chain antibody molecule of claim 1 .

9. A vector, which comprises the nucleic acid of claim 8 .

10. The vector of claim 9 , wherein said vector is an expression vector.

11. A host cell transformed or transfected with the vector of claim 10 .

12. A process for producing a bispecific single chain antibody molecule, said process comprising

culturing a host cell comprising a nucleic acid encoding the bispecific single chain antibody molecule under conditions allowing the expression of the bispecific single chain antibody molecule,

wherein the bispecific single chain antibody molecule comprises a first binding domain that specifically binds to human CD3 epsilon (CD3ε) chain and a second binding domain that specifically binds to human prostate-specific membrane antigen (PSMA),

wherein the first binding domain comprises a light chain variable (VL CD3ε) region comprising complementarity determining regions CDR-L1, CDR-L2, and CDR-L3 and a heavy chain variable (VH CD3ε) region comprising complementarity determining regions CDR-H1, CDR-H2, and CDR-H3, and wherein CDR-L1 has the sequence of SEQ ID NO: 171, CDR-L2 has the sequence of SEQ ID NO: 172, CDR-L3 has the sequence of SEQ ID NO: 173, CDR-H1 has the sequence of SEQ ID NO: 174, CDR-H2 has the sequence of SEQ ID NO: 175, and CDR-H3 has the sequence of SEQ ID NO: 176, and

recovering the produced molecule from the culture.

13. A pharmaceutical composition comprising the bispecific single chain antibody molecule of claim 1 .

14. The bispecific single chain antibody molecule of claim 1 , wherein the first binding domain is a single chain variable fragment (scFv) and the VH CD3ε region and the VL CD3ε region are connected by a peptide linker.

15. The bispecific single chain antibody molecule of claim 14 , wherein the VH CD3ε and VL CD3ε regions are arranged in an amino to carboxyl terminal order of VH CD3ε-VL CD3ε.

16. The bispecific single chain antibody molecule of claim 14 , wherein the first binding domain is positioned toward the carboxyl terminus of the molecule relative to the second binding domain.

17. The bispecific single chain antibody molecule of claim 1 , wherein the second binding domain is a single chain variable fragment (scFv) comprising a VH region and a VL region connected by a peptide linker.

18. The bispecific single chain antibody molecule of claim 1 , wherein the second binding domain comprises a VH region (VH PSMA) and VL region (VL PSMA), and wherein the variable regions in the bispecific single chain antibody molecule are arranged in an amino to carboxyl terminal order of VH PSMA-VL PSMA-VH CD3ε-VL CD3ε or VL PSMA-VH PSMA-VH CD3ε-VL CD3ε.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 26, 2021
From: KUFER, PETER; RAUM, TOBIAS; KISCHEL, ROMAN; LUTTERBUSE, RALF; HOFFMANN, PATRICK; RAU, DORIS; MANGOLD, SUSANNE; KLINGER, MATTHIAS; SCHALLER, EVELYNE; HAUSMANN, SUSANNE; FLUHR, PETRA; STEIGER, CAROLA
To: MICROMET AG
Reel/Frame 056356/0470 →
CHANGE OF NAME Recorded May 26, 2021
From: MICROMET AG
To: AMGEN RESEARCH (MUNICH) GMBH
Reel/Frame 056394/0226 →
Continuity (4)
Continuation 16020558 · Jun 27, 2018
Continuation 13122245
Provisional Application 61101857 · Oct 1, 2008
Related Publication 20230037742A1 · Feb 9, 2023
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Xu et al., In vitro characterization of five humanized OKT3 effector function variant antibodies, [cited by applicant]
Chang et al., Loop-sequence features and stability determinants in antibody variable domains by high-throughput experiments, [cited by applicant]
Schmittgen et al., Expression of prostate specific membrane antigen and three alternatively spliced variants of PSMA in prostate cancer patients, [cited by applicant]
Yu et al., Rationalization and design of the complementarity determining region sequences in an antibody-antigen recognition interface, [cited by applicant]
Amann et al., Therapeutic window of MuS110, a single-chain antibody construct bispecific for Murine EpCAM and murine CD3, [cited by applicant]
Dreier et al., Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody, [cited by applicant]
Ebelt et al., Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma, [cited by applicant]
Friedrich et al., Regression of human prostate cancer xenografts in mice by AMG 212/BAY2010112, a novel PSMA/CD3-Bispecific BiTE antibody cross-reactive with non-human primate antigens, [cited by applicant]
Gregorakis et al., Prostate-specific membrane antigen: current and future utility, [cited by applicant]
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Segal et al., Bispecific antibodies in cancer therapy, [cited by applicant]