US 12,215,155 B2Granted

Antibodies binding to CD3 and CD19

AssigneeHoffmann-La Roche Inc.

InventorsAnne Freimoser-Grundschober, Maria Valeria Gonzalez Nicolini, Ralf Hosse, Alexander Knaupp, Ekkehard Moessner, Wolfgang Richter, Halina Trochanowska, Pablo Umaña, Christian Klein, Inja Waldhauer

Life of this patent

Estimating the term…

patentgrep

Loading patent…

Abstract

The present invention generally relates to antibodies that bind to CD3 and CD19, e.g. for activating T cells. In addition, the present invention relates to polynucleotides encoding such antibodies, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the antibodies, and to methods of using them in the treatment of disease.

Claims64

Dependent claims

A method of treating an autoimmune disease in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21;
and
(c) an Fc domain composed of a first subunit and a second subunit;
wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

14 more elements

A method of treating an autoimmune disease in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the VH comprises the amino acid sequence of SEQ ID NO:
7 and the VL comprises the amino acid sequence of SEQ ID NO:
11;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain comprises a VH comprising the amino acid sequence of SEQ ID NO:
18 and a VL comprising the amino acid sequence of SEQ ID NO:
22;
and
(c) an Fc domain composed of a first subunit and a second subunit;
wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

6 more elements

A method of treating an autoimmune disease in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21;
and
(c) an Fc domain composed of a first subunit and a second subunit;
wherein in the constant domain CL of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) (numbering according to Kabat), and wherein in the constant domain CH1 of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index);
and wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

15 more elements

A method of treating lupus in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21;
and
(c) an Fc domain composed of a first subunit and a second subunit;
wherein in the constant domain CL of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) (numbering according to Kabat), and wherein in the constant domain CH1 of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index);
and wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

15 more elements

A method of treating SLE in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21;
and
(c) an Fc domain composed of a first subunit and a second subunit;
wherein in the constant domain CL of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) (numbering according to Kabat), and wherein in the constant domain CH1 of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index);
and wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

15 more elements

A method of treating LN in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21;
and
(c) an Fc domain composed of a first subunit and a second subunit;
wherein in the constant domain CL of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 124 is substituted by lysine (K) (numbering according to Kabat) and the amino acid at position 123 is substituted by arginine (R) (numbering according to Kabat), and wherein in the constant domain CH1 of each of the second antigen binding domain and the third antigen binding domain the amino acid at position 147 is substituted by glutamic acid (E) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted by glutamic acid (E) (numbering according to Kabat EU index);
and wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

15 more elements

A method of treating an autoimmune disease in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
7 and a VL comprising the amino acid sequence of SEQ ID NO:
11;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
18 and a VL comprising the amino acid sequence of SEQ ID NO:
22;
and
(c) an Fc domain composed of a first subunit and a second subunit, wherein the Fc domain is an IgG Fc domain;
wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

18 more elements

A method of treating lupus in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
7 and a VL comprising the amino acid sequence of SEQ ID NO:
11;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
18 and a VL comprising the amino acid sequence of SEQ ID NO:
22;
and
(c) an Fc domain composed of a first subunit and a second subunit, wherein the Fc domain is an IgG Fc domain;
wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

18 more elements

A method of treating SLE in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
7 and a VL comprising the amino acid sequence of SEQ ID NO:
11;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
18 and a VL comprising the amino acid sequence of SEQ ID NO:
22;
and
(c) an Fc domain composed of a first subunit and a second subunit, wherein the Fc domain is an IgG Fc domain;
wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

18 more elements

A method of treating LN in an individual, comprising administering to said individual an effective amount of an antibody that binds to CD3 and CD19, wherein the antibody comprises:

(a) a first antigen binding domain that binds to CD3, wherein the first antigen binding domain is a Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, and wherein the first antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
2, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
3, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
5, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
8, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
9, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
10, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
7 and a VL comprising the amino acid sequence of SEQ ID NO:
11;
(b) a second antigen binding domain and a third antigen binding domain that bind to CD19, wherein the second antigen binding domain and the third antigen binding domain are each a conventional Fab molecule, and wherein each of the second antigen binding domain and the third antigen binding domain (i) comprises a VH comprising an HCDR 1 comprising the amino acid sequence of SEQ ID NO:
15, an HCDR 2 comprising the amino acid sequence of SEQ ID NO:
16, and an HCDR 3 comprising the amino acid sequence of SEQ ID NO:
17, and a VL comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO:
19, an LCDR 2 comprising the amino acid sequence of SEQ ID NO:
20, and an LCDR 3 comprising the amino acid sequence of SEQ ID NO:
21, and/or (ii) comprises a VH comprising the amino acid sequence of SEQ ID NO:
18 and a VL comprising the amino acid sequence of SEQ ID NO:
22;
and
(c) an Fc domain composed of a first subunit and a second subunit, wherein the Fc domain is an IgG Fc domain;
wherein the second antigen binding domain is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the first antigen binding domain, and the first antigen binding domain and the third antigen binding domain are each fused at the C-terminus of the Fab heavy chain to the N-terminus of one of the subunits of the Fc domain.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 18/446,032Filed 8 Aug 2023 · division
Priority: EP 2018105619 Jun 2020
Published: US 2024/0132590 A125 Apr 2024
Granted: 4 Feb 2025
Term ends: Not estimatedThe source records don’t support an estimate.

Classification21 codes

C07K 16/2809
Against the immunoglobulin superfamily: against the T-cell receptor -CD3 complex
A61P 35/00
Antineoplastic agents
C07K 16/2803
Against receptors, cell surface antigens or cell surface determinants: against the immunoglobulin superfamily
C07K 16/30
Against receptors, cell surface antigens or cell surface determinants: from tumour cells

Family

Application17/350,111Parent of this division · filed 17 Jun 2021
US 2024/0132590 A1Pre-grant publication · published 25 Apr 2024
US 11,780,920 B2Parent of this division
US 2022/0010014 A1Published application
US 12,215,155 B2This patent

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

Timeline

Citations

Open elsewhere

Building an agent or pulling many patents? Use the API or MCP server instead of scraping pages. Get an API key