# US 8,784,821 B1 · Human-anti-human cd3 binding molecules

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- Number: US 8,784,821 B1
- Document ID: US8784821B1
- Status: Granted
- Kind: B1
- Application number: 10/554,731
- Filed: 2004-05-26
- Granted: 2014-07-22
- Earliest claimed: 2003-05-31
- Assignees: Amgen Research (Munich) GmbH
- Applicants: Peter Kufer; Tobias Raum; Meera Berry; Roman Kischel; Susanne Mangold; Eva Krinner; Birgit Kohleisen; Steven Zeman; Christian Itin; Patrick Bäuerle
- Inventors: Peter Kufer; Tobias Raum; Meera Berry; Roman Kischel; Susanne Mangold; Eva Krinner; Birgit Kohleisen; Steven Zeman; Christian Itin; Patrick Bäuerle
- Web page: https://patentgrep.com/patent/US8784821B1

## CPC

- C07K 16/24: against cytokines, lymphokines or interferons
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/31: multispecific
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention provides a method for the preparation of a human binding molecule, fragment or derivative thereof which specifically binds to the human CD3 complex. Furthermore, the invention provides a human binding molecules specifically binding to the human CD3 complex and means comprising said human binding molecules.

## Claims

### Claim 1

A purified binding molecule specifically binding to/interacting with the human CD3 complex, whereby said binding molecule is an antibody molecule, antibody fragment or derivative thereof or an antibody construct, wherein said antibody molecule, antibody fragment or derivative thereof or an antibody construct comprises a CDR1, CDR2 and CDR3 region, wherein said CDR regions comprise:
a) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 3, 5, and 7 or having the amino acid sequence as shown in SEQ ID NOs: 4, 6, and 8 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 11, 13, 15 or having the amino acid sequence as shown in SEQ ID NOs: 12, 14, and 16;
b) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 19, 21, and 23 or having the amino acid sequence as shown in SEQ ID NOs: 20, 22, and 24 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 27, 29, 31 or having the amino acid sequence as shown in SEQ ID NOs: 28, 30, and 32;
c) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 35, 37, and 39 or having the amino acid sequence as shown in SEQ ID NOs: 36, 38, and 40 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 43, 45, 47 or having the amino acid sequence as shown in SEQ ID NOs: 44, 46, and 48;
d) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 51, 53, and 55 or having the amino acid sequence as shown in SEQ ID NOs: 52, 54, and 56 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 59, 61, 63 or having the amino acid sequence as shown in SEQ ID NOs: 60, 62, and 64;
e) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 67, 69, and 71 or having the amino acid sequence as shown in SEQ ID NOs: 68, 70 and 72 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 75, 77, 79 or having the amino acid sequence as shown in SEQ ID NOs: 76, 78, and 80;
f) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 83, 85, and 87 or having the amino acid sequence as shown in SEQ ID NOs: 84, 86, and 88 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 91, 93, 95 or having the amino acid sequence as shown in SEQ ID NOs: 92, 94, and 96;
g) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 99, 101, and 103 or having the amino acid sequence as shown in SEQ ID NOs: 100, 102, and 104 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 107, 109, 111 or having the amino acid sequence as shown in SEQ ID NOs: 108, 110, and 112; or
h) VH-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 115, 117, and 119 or having the amino acid sequence as shown in SEQ ID NOs: 116, 118, and 120 and VL-region CDR1, CDR2 and CDR3 as encoded by a nucleic acid molecule as shown in SEQ ID NOs: 123, 125, 127 or having the amino acid sequence as shown in SEQ ID NOs: 124, 126, and 128.

### Claim 2 (depends on 1)

The human binding molecule of claim 1, wherein said derivative of an antibody is an scFv.

### Claim 3 (depends on 1)

The binding molecule according to claim 1, wherein said antibody molecule, antibody fragment or derivative thereof or an antibody construct, comprises a variable VH-region as encoded by a nucleic acid molecule as shown in a SEQ ID NO selected from the group consisting of SEQ ID NOs: 1, 17, 33, 49, 65, 81, 97 and 113 or a variable VH-region having an amino acid sequence as shown in a SEQ ID NO selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98 and 114.

### Claim 4 (depends on 1)

The binding molecule according to claim 1, wherein said antibody molecule, antibody fragment or derivative thereof or an antibody construct, comprises a variable VL-region as encoded by a nucleic acid molecule as shown in a SEQ ID NO selected from the group consisting of SEQ ID NOs: 9, 25, 41, 57, 73, 89, 105 and 121 or a variable VL-region having an amino acid sequence as shown in a SEQ ID NO selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106 and 122.

### Claim 5 (depends on 1)

The binding molecule of claim 1, additionally comprising at least one further antigen-interaction-site and/or at least one further effector domain.

### Claim 6 (depends on 5)

The binding molecule according to claim 5, which is humanized and/or deimmunized.

### Claim 7 (depends on 5)

The binding molecule of claim 5, wherein said at least one further antigen-interaction-site is specific for one or more cell surface molecule.

### Claim 8 (depends on 7)

The binding molecule according to claim 7, wherein said cell surface molecule is a tumor specific marker.

### Claim 9 (depends on 5)

The binding molecule of claim 5, wherein said at least one further antigen-interaction-site is a scFv.

### Claim 10 (depends on 5)

The binding molecule according to claim 5, wherein said at least one further antigen-interaction-site specifically binds to/interacts with an antigen selected from the group consisting of EpCAM, CCR5, CD19, EphA2, HER-2 neu, HER-3, HER-4, EGFR, PSMA, CEA, MUC-1 (mucin), MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC7, βhCG, Lewis-Y, CD20, CD33, CD30, ganglioside GD3, 9-O-Acetyl-GD3, GM2, Globo H, fucosyl GM1, Poly SA, GD2, Carboanhydrase IX (MN/CA IX), CD44v6, Sonic Hedgehog (Shh), Wue-1, Plasma Cell Antigen, (membrane-bound) IgE, Melanoma Chondroitin Sulfate Proteoglycan (MCSP), CCR8, TNF-alpha precursor, STEAP, mesothelin, A33 Antigen, Prostate Stem Cell Antigen (PSCA), Ly-6, desmoglein 4, E-cadherin neoepitope, Fetal Acetylcholine Receptor, CD25, CA19-9 marker, CA-125 marker and Muellerian Inhibitory Substance (MIS) Receptor type II, sTn (sialylated Tn antigen; T AG-72), FAP (fibroblast activation antigen), endosialin, EGFRvIII, LG, SAS and CD63.

### Claim 11 (depends on 10)

The binding molecule according to claim 10, wherein said further antigen binding site specifically binds to/interacts with the CD 19 molecule.

### Claim 12 (depends on 11)

The binding molecule according to claim 11, comprising an amino acid sequence selected from the group of
(a) an amino acid sequence corresponding to construct 1prot to 64prot of table 2;
(b) an amino acid sequence encoded by a nucleic acid sequence corresponding to construct 1nuc to 64nuc of table 1;
(c) an amino acid sequence encoded by a nucleic acid sequence hybridizing with the complementary strand of a nucleic acid sequence as defined In (b) under stringent hybridization conditions; and
(d) an amino acid sequence encoded by a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence of anyone of (b) and (c).

### Claim 13 (depends on 10)

The binding molecule according to claim 10, wherein said further antigen binding site specifically binds to/interacts with the EpCAM molecule.

### Claim 14 (depends on 13)

The binding molecule according to claim 13, comprising an amino acid sequence selected from the group of
(a) an amino acid sequence corresponding to construct 65prot to 128prot of table 4;
(b) an amino acid sequence encoded by a nucleic acid sequence corresponding to construct 65nuc to 128nuc of in table 3;
(c) an amino acid sequence encoded by a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence of (b).

### Claim 15 (depends on 10)

The binding molecule according to claim 10, wherein said further antigen binding site specifically binds to/interacts with the CCR5 molecule.

### Claim 16 (depends on 15)

The binding molecule according to claim 15, comprising an amino acid sequence selected from the group of
(a) an amino acid sequence corresponding to construct 129prot to 192prot of table 6;
(b) an amino acid sequence encoded by a nucleic acid sequence corresponding to construct 129nuc to 192nuc of table 5;
(c) an amino acid sequence encoded by a nucleic acid sequence hybridizing with the complementary strand of a nucleic acid sequence as defined in (b) under stringent hybridization conditions; and
(d) an amino acid sequence encoded by a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence of anyone of (b) and (c).

### Claim 17 (depends on 10)

The binding molecule according to claim 10, wherein said further antigen binding site specifically binds to/interacts with the CD20 molecule.

### Claim 18 (depends on 17)

The binding molecule according to claim 17, comprising an amino acid sequence selected from the group of
(a) an amino acid sequence corresponding to construct 193prot to 256prot of table 8;
(b) an amino acid sequence encoded by a nucleic acid sequence corresponding to construct 193nuc to 256nuc of table 7;
(c) an amino acid sequence encoded by a nucleic acid sequence hybridizing with the complementary strand of a nucleic acid sequence as defined in (b) under stringent hybridization conditions; and
(d) an amino acid sequence encoded by a nucleic acid sequence which is degenerate as a result of the genetic code to a nucleotide sequence of anyone of (b) and (c).

### Claim 19 (depends on 1)

A composition comprising a binding molecule according to claim 1.

### Claim 20 (depends on 19)

The composition of claim 19 which is a pharmaceutical composition further comprising, optionally, suitable formulations of carrier, stabilizers and/or excipients.

### Claim 21 (depends on 19)

The composition of claim 19 which is a diagnostic composition further comprising, optionally, means and methods for detection.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14)

A kit comprising a binding molecule according to any one of claims 1 to 4 or claims 5 to 10, 13 and 14.

### Claim 23 (depends on 19)

The composition of claim 19, further comprising a proteinaceous compound capable of providing an activation signal for immune effector cells.