# US 12,215,155 B2 · Antibodies binding to CD3 and CD19

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- Number: US 12,215,155 B2
- Document ID: US12215155B2
- Status: Granted
- Kind: B2
- Application number: 18/446,032
- Filed: 2023-08-08
- Published: 2024-04-25
- Granted: 2025-02-04
- Earliest claimed: 2020-06-19
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Anne Freimoser-Grundschober; Maria Valeria Gonzalez Nicolini; Ralf Hosse; Alexander Knaupp; Ekkehard Moessner; Wolfgang Richter; Halina Trochanowska; Pablo Umaña; Christian Klein; Inja Waldhauer
- Web page: https://patentgrep.com/patent/US12215155B2

## CPC

- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- A61P 35/00: Antineoplastic agents
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/30: from tumour cells
- A61K 2039/505: {comprising antibodies}
- C07K 2317/31: multispecific
- C07K 2317/40: characterized by post-translational modification
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/55: Fab or Fab'
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/64: comprising a combination of variable region and constant region components
- C07K 2317/66: comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
- C07K 2317/70: characterized by effect upon binding to a cell or to an antigen
- C07K 2317/71: Decreased effector function due to an Fc-modification
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/00: Fusion polypeptide
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
(a) the first antigen binding domain comprises a VH comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7 and a VL comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; and
(b) each of the second antigen binding domain and the third antigen binding domain comprises a VH comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18 and a VL comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 22.

### Claim 3 (depends on 1)

The method of claim 1, 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 lysine (K) or 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).

### Claim 4 (depends on 1)

The method of claim 1, wherein the Fc domain is an IgG Fc domain.

### Claim 5 (depends on 1)

The method of claim 1, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 6 (depends on 1)

The method of claim 1, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 7 (depends on 1)

The method of claim 1, wherein the autoimmune disease is lupus.

### Claim 8 (depends on 7)

The method of claim 7, wherein the lupus is systemic lupus erythematosus (SLE) or lupus nephritis (LN).

### Claim 9

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.

### Claim 10 (depends on 9)

The method of claim 9, 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 lysine (K) or 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).

### Claim 11 (depends on 9)

The method of claim 9, wherein the Fc domain is an IgG Fc domain.

### Claim 12 (depends on 9)

The method of claim 9, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 13 (depends on 9)

The method of claim 9, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 14 (depends on 9)

The method of claim 9, wherein the autoimmune disease is lupus.

### Claim 15 (depends on 14)

The method of claim 14, wherein the lupus is SLE or LN.

### Claim 16

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 polypeptide comprising the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 27.

### Claim 17 (depends on 16)

The method of claim 16, wherein the autoimmune disease is lupus.

### Claim 18 (depends on 17)

The method of claim 17, wherein the lupus is SLE or LN.

### Claim 19

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.

### Claim 20 (depends on 19)

The method of claim 19, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 21 (depends on 20)

The method of claim 20, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 22

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.

### Claim 23 (depends on 22)

The method of claim 22, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 24 (depends on 22)

The method of claim 22, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 25

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.

### Claim 26 (depends on 25)

The method of claim 25, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 27 (depends on 25)

The method of claim 25, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 28

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.

### Claim 29 (depends on 28)

The method of claim 28, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 30 (depends on 28)

The method of claim 28, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 31

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.

### Claim 32 (depends on 31)

The method of claim 31, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 33 (depends on 31)

The method of claim 31, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 34

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.

### Claim 35 (depends on 34)

The method of claim 34, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 36 (depends on 34)

The method of claim 34, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 37

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.

### Claim 38 (depends on 37)

The method of claim 37, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 39 (depends on 37)

The method of claim 37, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 40

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.

### Claim 41 (depends on 40)

The method of claim 40, wherein the Fc domain is a human IgG1 Fc domain, and wherein in the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W) and the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V), the threonine residue at position 366 is replaced with a serine residue (T366S), the leucine residue at position 368 is replaced with an alanine residue (L368A), and the tyrosine residue at position 349 is replaced with a cysteine residue (Y349C) (numbering according to Kabat EU index), and wherein further in each of the first subunit and the second subunit of the Fc domain the leucine residue at position 234 is replaced with an alanine residue (L234A), the leucine residue at position 235 is replaced with an alanine residue (L235A), and the proline residue at position 329 is replaced by a glycine residue (P329G) (numbering according to Kabat EU index).

### Claim 42 (depends on 40)

The method of claim 40, wherein the antibody comprises a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 39, a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24, two polypeptides each comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25, and a polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27.

### Claim 43 (depends on 1)

The method of claim 1, 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 via a peptide linker.

### Claim 44 (depends on 43)

The method of claim 43, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 45 (depends on 9)

The method of claim 9, 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 via a peptide linker.

### Claim 46 (depends on 45)

The method of claim 45, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 47 (depends on 16)

The method of claim 16, 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 via a peptide linker.

### Claim 48 (depends on 47)

The method of claim 47, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 49 (depends on 19)

The method of claim 19, 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 via a peptide linker.

### Claim 50 (depends on 49)

The method of claim 49, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 51 (depends on 22)

The method of claim 22, 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 via a peptide linker.

### Claim 52 (depends on 51)

The method of claim 51, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 53 (depends on 25)

The method of claim 25, 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 via a peptide linker.

### Claim 54 (depends on 53)

The method of claim 53, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 55 (depends on 28)

The method of claim 28, 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 via a peptide linker.

### Claim 56 (depends on 55)

The method of claim 55, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 57 (depends on 31)

The method of claim 31, 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 via a peptide linker.

### Claim 58 (depends on 57)

The method of claim 57, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 59 (depends on 34)

The method of claim 34, 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 via a peptide linker.

### Claim 60 (depends on 59)

The method of claim 59, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 61 (depends on 37)

The method of claim 37, 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 via a peptide linker.

### Claim 62 (depends on 61)

The method of claim 61, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).

### Claim 63 (depends on 40)

The method of claim 40, 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 via a peptide linker.

### Claim 64 (depends on 63)

The method of claim 63, wherein the peptide linker comprises the amino acid sequence GGGGSGGGGS (SEQ ID NO: 48).