Anti-CD3 antibodies and methods of use

• US 10,640,572 B2
• Filed: 03/29/2017
• Issued: 05/05/2020
• Est. Priority Date: 12/17/2013
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Chen, Xiaocheng, Dennis, Mark S., Ebens, Jr., Allen J., Junttila, Teemu T., Kelley, Robert F., Mathieu, Mary A.
• Primary Examiner(s): Skelding, Zachary S
• Application Number:
  US15/473,242
• Publication Number:
  US 20170204194A1
• Time in Patent Office: 1,133 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: 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
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/283 : against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 16/2863 : against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/522 : CH1 domain
• CPC Class Codes: C07K 2317/524 : CH2 domain
• CPC Class Codes: C07K 2317/526 : CH3 domain
• CPC Class Codes: C07K 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

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

Claims

1. A bispecific antibody that binds to HER2 and CD3, wherein the bispecific antibody comprises:

(a) an anti-HER2 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;

169,

an HVR-H2 comprising the amino acid sequence of SEQ ID NO;

170,

an HVR-H3 comprising the amino acid sequence of SEQ ID NO;

171,

an HVR-L1 comprising the amino acid sequence of SEQ ID NO;

172,

an HVR-L2 comprising the amino acid sequence of SEQ ID NO;

173, and

an HVR-L3 comprising the amino acid sequence of SEQ ID NO;

174; 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.

2. The bispecific antibody 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;

270;

(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;

271;

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).

3. The bispecific antibody of claim 1, wherein the first binding domain binds to a human CD3ε

polypeptide or a cynomolgus monkey (cyno) CD3ε

polypeptide.

4. The bispecific antibody of claim 1, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function.

5. The bispecific antibody of claim 1, wherein the bispecific antibody comprises one or more substitution mutations substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).

6. The bispecific antibody of claim 5, wherein the one or more substitution mutations comprises N297G, N297A, L234A, L235A, and/or D265A.

7. The bispecific antibody of claim 4, wherein the substitution mutation is an aglycosylation site mutation.

8. The bispecific antibody of claim 7, wherein the aglycosylation site mutation is at amino acid residue N297 (EU numbering).

9. The bispecific antibody of claim 8, wherein the aglycosylation site mutation is N297G or N297A.

10. The bispecific antibody of claim 1, wherein the bispecific antibody comprises a first CH1 (CH1₁) domain, a first CH2 (CH2₁) domain, a first CH3 (CH3₁) domain, a second CH1 (CH1₂) domain, a second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain, wherein

the CH3₁ domain is paired with the CH3₂ domain, wherein the CH3₁ and CH3₂ domains each comprise a knob or hole, and wherein the knob or hole in the CH3₁ domain is positionable in the hole or knob, respectively, in the CH3₂ domain.

11. The bispecific antibody of claim 1, wherein the bispecific antibody is monoclonal, humanized, or chimeric.

12. The bispecific antibody of claim 1, wherein the bispecific antibody is an antibody fragment that binds HER2 and CD3.

13. The bispecific antibody of claim 1, wherein the bispecific antibody is a full-length antibody.

14. A composition comprising the bispecific antibody of claim 1.

15. A kit comprising:

(a) the composition of claim 14; and

(b) a package insert comprising instructions for administering the composition to a subject to treat or delay progression of a cell proliferative disorder.

18. A kit comprising:

(a) the composition of claim 14; and

(b) a package insert comprising instructions for administering the composition to a subject to treat or delay progression of a HER2-positive cancer.

16. A bispecific antibody that binds to HER2 and CD3, wherein the bispecific antibody comprises an anti-HER2 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:

270 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO;

271, and an anti-CD3 arm comprising a second 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.

17. A bispecific antibody that binds to HER2 and CD3, wherein the bispecific antibody comprises an anti-HER2 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:

270 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO;

271, and an anti-CD3 arm comprising a second 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, wherein the bispecific antibody comprises the substitution mutation N297G; and

wherein;

(a) the anti-HER2 arm further comprises a CH1₁ domain, a CH2₁ domain, a CH3₁ domain;

(b) the anti-CD3 arm further comprises a CH1₂ domain, a CH2₂ domain, and a CH3₂ domain, wherein the CH3₁ domain is paired with the CH3₂ domain; and

(c) the CH3₁ domain comprises a knob, the CH3₂ domain comprises a hole, and the knob is positionable in the hole.