# US 10,865,251 B2 · Anti-CD3 antibodies and methods of use

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- Number: US 10,865,251 B2
- Document ID: US10865251B2
- Status: Granted
- Kind: B2
- Application number: 16/144,452
- Filed: 2018-09-27
- Published: 2019-04-18
- Granted: 2020-12-15
- Earliest claimed: 2013-12-17
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Xiaocheng Chen; Mark S. Dennis; Allen J. Ebens, Jr.; Robert F. Kelley; Mary A. Mathieu; Liping L. Sun
- Web page: https://patentgrep.com/patent/US10865251B2

## CPC

- C07K 16/32: against translation products of oncogenes
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/6881: {Cluster-antibody conjugates, i.e. the modifying agent consists of a plurality of antibodies covalently linked to each other or of different antigen-binding fragments covalently linked to each other}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 16/283: {against Fc-receptors, e.g. CD16, CD32, CD64 (CD23 C07K16/2851)}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2887: {against CD20}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- A61K 2039/505: {comprising antibodies}
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/522: CH1 domain
- C07K 2317/524: CH2 domain
- C07K 2317/526: CH3 domain
- C07K 2317/54: F(ab')2
- C07K 2317/55: Fab or Fab'
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/622: Single chain antibody (scFv)
- 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: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides anti-cluster of differentiation 3 (CD3) antibodies and methods of using the same.

## Claims

### Claim 1

One or more isolated nucleic acids encoding a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises:
(a) an anti-CD20 arm comprising a first binding domain, the first binding domain comprising:
a hypervariable region (HVR)-H1 comprising the amino acid sequence of SEQ ID NO: 157,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162; and
(b) an anti-CD3 arm comprising a second binding domain, the second binding domain comprising:
an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1,
an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2,
an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3,
an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4,
an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and
an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

### Claim 2 (depends on 1)

The one or more nucleic acids of claim 1, wherein the first binding domain comprises:
(a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 266; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b),
and the second binding domain comprises:
(a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 184; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 185; or (c) a VH domain as in (a) and a VL domain as in (b).

### Claim 3 (depends on 1)

The one or more nucleic acids of claim 1, wherein the second binding domain binds to a human CD3ε polypeptide.

### Claim 4 (depends on 1)

The one or more nucleic acids of claim 1, wherein the second binding domain binds to a cynomolgus monkey (cyno) CD3ε polypeptide.

### Claim 5 (depends on 1)

The one or more nucleic acids of claim 1, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

### Claim 6 (depends on 5)

The one or more nucleic acids of claim 5, wherein the substitution mutation is an aglycosylation site mutation.

### Claim 7 (depends on 6)

The one or more nucleic acids of claim 6, wherein the aglycosylation site mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).

### Claim 8 (depends on 7)

The one or more nucleic acids of claim 7, wherein the aglycosylation site mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A.

### Claim 9 (depends on 1)

The one or more nucleic acids of claim 1, wherein the bispecific antibody is monoclonal, humanized, or chimeric.

### Claim 10 (depends on 9)

The one or more nucleic acids of claim 9, wherein the bispecific antibody is an antibody fragment that binds CD20 and CD3.

### Claim 11 (depends on 10)

The one or more nucleic acids of claim 10, wherein the antibody fragment is a Fab, Fab′-SH, Fv, scFv, or (Fab′)2 fragment.

### Claim 12 (depends on 9)

The one or more nucleic acids of claim 9, wherein the bispecific antibody is a full-length antibody.

### Claim 13 (depends on 1)

A vector comprising the one or more isolated nucleic acids of claim 1.

### Claim 14 (depends on 1)

A host cell comprising a vector, wherein the vector comprises the one or more isolated nucleic acids of claim 1.

### Claim 15

One or more isolated nucleic acids encoding a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185, and an anti-CD20 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267.

### Claim 16 (depends on 15)

A vector comprising the one or more isolated nucleic acids of claim 15.

### Claim 17 (depends on 15)

A host cell comprising a vector, wherein the vector comprises the one or more isolated nucleic acids of claim 15.

### Claim 18

One or more isolated nucleic acids encoding a bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185, and an anti-CD20 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267, wherein (a) the anti-CD3 arm comprises T366S, L368A, Y407V, and N297G substitution mutations and (b) the anti-CD20 arm comprises T366W and N297G substitution mutations.

### Claim 19 (depends on 18)

A vector comprising the one or more isolated nucleic acids of claim 18.

### Claim 20 (depends on 18)

A host cell comprising a vector, wherein the vector comprises the one or more isolated nucleic acids of claim 18.