# US 10,766,967 B2 · Bispecific T cell activating antigen binding molecules

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- Number: US 10,766,967 B2
- Document ID: US10766967B2
- Status: Granted
- Kind: B2
- Application number: 15/281,484
- Filed: 2016-09-30
- Published: 2017-07-06
- Granted: 2020-09-08
- Earliest claimed: 2015-10-02
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Marina Bacac; Tanja Fauti; Sabine Imhof-Jung; Christian Klein; Stefan Klostermann; Ekkehard Moessner; Michael Molhoj; Christiane Neumann; Joerg Thomas Regula; Wolfgang Schaefer; Pablo Umana
- Web page: https://patentgrep.com/patent/US10766967B2

## CPC

- C07K 16/3007: {Carcino-embryonic Antigens}
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/35: Valency
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/522: CH1 domain
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/66: comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
- 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 novel bispecific antigen binding molecules for T cell activation and re-direction to specific target cells. In addition, the present invention relates to polynucleotides encoding such bispecific antigen binding molecules, and vectors and host cells comprising such polynucleotides. The invention further relates to methods for producing the bispecific antigen binding molecules of the invention, and to methods of using these bispecific antigen binding molecules in the treatment of disease.

## Claims

### Claim 1

A T cell activating bispecific antigen-binding molecule comprising:
(a) a first Fab molecule which specifically binds to a first antigen;
(b) a second Fab molecule which specifically binds to a second antigen, and wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other;
wherein the first antigen is CD3 and the second antigen is CEA, or the first antigen is CEA and the second antigen is CD3;
wherein the Fab molecule which specifically binds to CD3 comprises a heavy chain variable region comprising the heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 4, the HCDR 2 of SEQ ID NO: 5, and the HCDR 3 of SEQ ID NO: 6, and a light chain variable region comprising the light chain complementarity determining region (LCDR) 1 of SEQ ID NO: 8, the LCDR 2 of SEQ ID NO: 9, and the LCDR 3 of SEQ ID NO: 10; and
wherein the Fab molecule which specifically binds to CEA comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23.

### Claim 2 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, wherein the CD3 is CD3 epsilon.

### Claim 3 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, wherein the Fab molecule which specifically binds to CD3 comprises a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7.

### Claim 4 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, further comprising a third Fab molecule which specifically binds to the first antigen.

### Claim 5 (depends on 4)

The T cell activating bispecific antigen-binding molecule of claim 4, wherein the third Fab molecule is identical to the first Fab molecule.

### Claim 6 (depends on 4)

The T cell activating bispecific antigen-binding molecule of claim 4, wherein the first Fab molecule and the third Fab molecule specifically bind to CEA, and the second Fab molecule specifically binds to CD3.

### Claim 7 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, additionally comprising an Fc domain comprising a first subunit and a second subunit capable of stable association.

### Claim 8 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, wherein the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule.

### Claim 9 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, wherein the second Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit or the second subunit of the Fc domain.

### Claim 10 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, further comprising a third Fab molecule which specifically binds to the first antigen, wherein the third Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the first subunit or the second subunit of the Fc domain.

### Claim 11 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, further comprising a third Fab molecule which specifically binds to the first antigen, wherein the second Fab molecule and the third Fab molecule 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, and the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule.

### Claim 12 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, wherein the Fc domain is an IgG Fc domain.

### Claim 13 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, wherein the Fc domain is a human Fc domain.

### Claim 14 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, wherein the Fc domain comprises a modification promoting the association of the first subunit and the second subunit of the Fc domain.

### Claim 15 (depends on 14)

The T cell activating bispecific antigen-binding molecule of claim 14, wherein in the CH3 domain of the first subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is positionable.

### Claim 16 (depends on 15)

The T cell activating bispecific antigen-binding molecule of claim 15, wherein in the CH3 domain of the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W), and in the CH3 domain of the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V) (numberings according to Kabat EU index).

### Claim 17 (depends on 16)

The T cell activating bispecific antigen-binding molecule of claim 16, wherein in the first subunit of the Fc domain additionally the serine residue at position 354 is replaced with a cysteine residue (S354C) or the glutamic acid residue at position 356 is replaced with a cysteine residue (E356C), and in the second subunit of the Fc domain additionally the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C) (numberings according to Kabat EU index).

### Claim 18 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, wherein the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor and/or effector function.

### Claim 19 (depends on 18)

The T cell activating bispecific antigen-binding molecule of claim 18, wherein said one or more amino acid substitution is at one or more position selected from the group consisting of L234, L235, and P329 (numberings according to Kabat EU index).

### Claim 20 (depends on 7)

The T cell activating bispecific antigen-binding molecule of claim 7, wherein each subunit of the Fc domain comprises the amino acid substitutions L234A, L235A, and P329G (numberings according to Kabat EU index).

### Claim 21 (depends on 1)

One or more isolated polynucleotide encoding the T cell activating bispecific antigen-binding molecule of claim 1.

### Claim 22 (depends on 21)

A host cell comprising the polynucleotide(s) of claim 21.

### Claim 23 (depends on 22)

A method of producing a T cell activating bispecific antigen-binding molecule, the method comprising culturing the host cell of claim 22 under conditions suitable for the expression of the T cell activating bispecific antigen-binding molecule, wherein the T cell activating bispecific antigen-binding molecule comprises:
(a) a first Fab molecule which specifically binds to a first antigen;
(b) a second Fab molecule which specifically binds to a second antigen, and wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other;
wherein the first antigen is CD3 and the second antigen is CEA, or the first antigen is CEA and the second antigen is CD3;
wherein the Fab molecule which specifically binds to CD3 comprises a heavy chain variable region comprising the HCDR 1 of SEQ ID NO: 4, the HCDR 2 of SEQ ID NO: 5, and the HCDR 3 of SEQ ID NO: 6, and a light chain variable region comprising the LCDR 1 of SEQ ID NO: 8, the LCDR 2 of SEQ ID NO: 9, and the LCDR 3 of SEQ ID NO: 10; and
wherein the Fab molecule which specifically binds to CEA comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23.

### Claim 24 (depends on 23)

The T cell activating bispecific antigen-binding molecule produced by the method of claim 23.

### Claim 25 (depends on 1)

A pharmaceutical composition comprising the T cell activating bispecific antigen-binding molecule of claim 1 and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 6)

The T cell activating bispecific antigen-binding molecule of claim 6, wherein the CD3 is CD3 epsilon.

### Claim 27 (depends on 12)

The T cell activating bispecific antigen-binding molecule of claim 12, wherein the IgG Fc domain is an IgG1 Fc domain or an IgG4 Fc domain.

### Claim 28 (depends on 16)

The T cell activating bispecific antigen-binding molecule of claim 16, wherein in the second subunit of the Fc domain the threonine residue at position 366 is replaced with a serine residue (T366S) and the leucine residue at position 368 is replaced with an alanine residue (L368A) (numberings according to Kabat EU index).

### Claim 29 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, wherein the Fab molecule which specifically binds to CD3 comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7.

### Claim 30 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, wherein the first Fab molecule is a conventional Fab molecule.

### Claim 31 (depends on 4)

The T cell activating bispecific antigen-binding molecule of claim 4, wherein the third Fab molecule is a conventional Fab molecule.

### Claim 32 (depends on 1)

The T cell activating bispecific antigen-binding molecule of claim 1, wherein (i) in the constant domain CL of the first Fab molecule the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat), and in the constant domain CH1 of the first Fab molecule the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index); or (ii) in the constant domain CL of the second Fab molecule the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat), and in the constant domain CH1 of the second Fab molecule the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

### Claim 33 (depends on 32)

The T cell activating bispecific antigen-binding molecule of claim 32, wherein in the constant domain CL of the first Fab molecule the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat) and the amino acid at position 123 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat), and wherein in the constant domain CH1 of the first Fab molecule the amino acid at position 147 is substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index) and the amino acid at position 213 is substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

### Claim 34 (depends on 33)

The T cell activating bispecific antigen-binding molecule of claim 33, wherein in the constant domain CL of the first Fab molecule 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 the first Fab molecule 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 35

A T cell activating bispecific antigen-binding molecule, comprising:
(a) a first Fab molecule which specifically binds to a first antigen;
(b) a second Fab molecule which specifically binds to a second antigen, and wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other;
(c) a third Fab molecule which specifically binds to the first antigen; and
(d) an Fc domain composed of a first and a second subunit capable of stable association;
wherein the first antigen is CEA and the second antigen is CD3;
wherein the third Fab molecule is identical to the first Fab molecule;
wherein the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule, and the second Fab molecule and the third Fab molecule 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;
wherein the first Fab molecule and the third Fab molecule comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23; and
wherein the second Fab molecule comprises a heavy chain variable region comprising the HCDR 1 of SEQ ID NO: 4, the HCDR 2 of SEQ ID NO: 5, the HCDR 3 of SEQ ID NO: 6, and a light chain variable region comprising the LCDR 1 of SEQ ID NO: 8, the LCDR 2 of SEQ ID NO: 9, and the LCDR 3 of SEQ ID NO: 10.

### Claim 36 (depends on 35)

The T cell activating bispecific antigen-binding molecule of claim 35, wherein the second Fab molecule comprises a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7.

### Claim 37 (depends on 35)

The T cell activating bispecific antigen-binding molecule of claim 35, wherein:
(a) the Fc domain is a human IgG1 Fc domain;
(b) the first subunit of the Fc domain comprises amino acid substitutions S354C and T366W, and the second subunit of the Fc domain comprises amino acid substitutions Y3490, T366S, L368A, and Y407V; and
(c) each subunit of the Fc domain comprises the amino acid substitutions L234A, L235A, and P329G (numberings according to Kabat EU index).

### Claim 38 (depends on 35)

A pharmaceutical composition comprising the T cell activating bispecific antigen-binding molecule of claim 35.

### Claim 39 (depends on 35)

The T cell activating bispecific antigen-binding molecule of claim 35, wherein the second Fab molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7.

### Claim 40 (depends on 35)

The T cell activating bispecific antigen-binding molecule of claim 35, wherein in the constant domain CL of the first Fab molecule and the third Fab molecule 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 the first Fab molecule and the third Fab molecule 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 41

A T cell activating bispecific antigen-binding molecule, comprising:
(a) a first Fab molecule which specifically binds to a first antigen;
(b) a second Fab molecule which specifically binds to a second antigen, and wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other;
(c) a third Fab molecule which specifically binds to the first antigen; and
(d) an Fc domain composed of a first and a second subunit capable of stable association;
wherein the first antigen is CEA and the second antigen is CD3;
wherein the third Fab molecule is identical to the first Fab molecule;
wherein the first Fab molecule is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second Fab molecule, and the second Fab molecule and the third Fab molecule 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;
wherein the first Fab molecule and the third Fab molecule comprise a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23;
wherein the second Fab molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and
wherein:
(a) the Fc domain is a human IgG1 Fc domain;
(b) the first subunit of the Fc domain comprises amino acid substitutions S354C and T366W, and the second subunit of the Fc domain comprises amino acid substitutions Y3490, T366S, L368A, and Y407V; and
(c) each subunit of the Fc domain comprises the amino acid substitutions L234A, L235A, and P329G (numberings according to Kabat EU index).

### Claim 42 (depends on 41)

The T cell activating bispecific antigen-binding molecule of claim 41, comprising a polypeptide that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34, a polypeptide that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36, a polypeptide that is at least 95% identical to the amino acid sequence of SEQ ID NO: 37, and a polypeptide that is at least 95% identical to the amino acid sequence of SEQ ID NO: 38.

### Claim 43 (depends on 41)

A pharmaceutical composition comprising the T cell activating bispecific antigen-binding molecule of claim 41.

### Claim 44 (depends on 41)

The T cell activating bispecific antigen-binding molecule of claim 41, comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 34, a polypeptide comprising the amino acid sequence of SEQ ID NO: 36, a polypeptide comprising the amino acid sequence of SEQ ID NO: 37, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 38.

### Claim 45 (depends on 41)

The T cell activating bispecific antigen-binding molecule of claim 41, wherein in the constant domain CL of the first Fab molecule and the third Fab molecule 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 the first Fab molecule and the third Fab molecule 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 46

A T cell activating bispecific antigen-binding molecule comprising:
(a) a first antigen-binding moiety and a third antigen-binding moiety, each of which specifically binds to CEA; wherein each of the first antigen-binding moiety and the third antigen-binding moiety is a conventional Fab molecule comprising:
(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22; and
(ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 23, and wherein in the constant domain CL 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 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);
(b) a second antigen-binding moiety which specifically binds to CD3; wherein the second antigen-binding moiety is a crossover Fab molecule wherein the variable domains VL and VH of the Fab light chain and the Fab heavy chain are replaced by each other, wherein the second antigen-binding moiety comprises:
(i) a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3, wherein the amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3 comprises the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, and the HCDR3 of SEQ ID NO: 6; and
(ii) a light chain variable region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7, wherein the amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7 comprises the LCDR1 of SEQ ID NO: 8, the LCDR2 of SEQ ID NO: 9, and the LCDR3 of SEQ ID NO: 10; and
(c) an Fc domain composed of a first and a second subunit capable of stable association, wherein the Fc domain is a human IgG1 Fc domain, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W, the second subunit of the Fc domain comprises the amino acid substitutions Y3490, T366S, L368A, and Y407V, and wherein each subunit of the Fc domain comprises the amino acid substitutions L234A, L235A, and P329G (numberings according to Kabat EU index),
wherein the second and the third antigen-binding moiety 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, and the first antigen-binding moiety is fused at the C-terminus of the Fab heavy chain to the N-terminus of the Fab heavy chain of the second antigen-binding moiety.

### Claim 47 (depends on 46)

The T cell activating bispecific antigen-binding molecule of claim 46, wherein the second antigen-binding moiety comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7.

### Claim 48 (depends on 46)

The T cell activating bispecific antigen-binding molecule of claim 46, comprising a polypeptide that is at least 95% identical to the sequence of SEQ ID NO: 34, a polypeptide that is at least 95% identical to the sequence of SEQ ID NO: 36, a polypeptide that is at least 95% identical to the sequence of SEQ ID NO: 37, and a polypeptide that is at least 95% identical to the sequence of SEQ ID NO: 38.

### Claim 49 (depends on 46)

The T cell activating bispecific antigen-binding molecule of claim 46, comprising a polypeptide comprising the amino acid sequence of SEQ ID NO: 34, a polypeptide comprising the amino acid sequence of SEQ ID NO: 36, a polypeptide comprising the amino acid sequence of SEQ ID NO: 37, and a polypeptide comprising the amino acid sequence of SEQ ID NO: 38.

### Claim 50 (depends on 49)

A pharmaceutical composition comprising the T cell activating bispecific antigen-binding molecule of claim 49.