# US 10,865,248 B2 · Antigen binding complex having agonistic activity and methods of use

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- Number: US 10,865,248 B2
- Document ID: US10865248B2
- Status: Granted
- Kind: B2
- Application number: 15/725,208
- Filed: 2017-10-04
- Published: 2018-01-25
- Granted: 2020-12-15
- Earliest claimed: 2015-04-07
- Assignees: Genentech, Inc.
- Applicants: Genentech, Inc.
- Inventors: Greg Lazar; Jeong Kim; Jing Zhu; Yanli Yang; Randall Brezski
- Web page: https://patentgrep.com/patent/US10865248B2

## CPC

- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- A61K 38/02: Peptides of undefined number of amino acids; Derivatives thereof
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- 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 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- 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 2317/524: CH2 domain
- C07K 2317/526: CH3 domain
- 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 2317/75: Agonist effect on antigen
- 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

Provided herein are antigen binding polypeptides and complexes thereof having agonist activity. Also provided are methods for screening for complexes or polypeptides having agonist activity, enhancing the agonist activity of a polypeptide, and for agonizing a cell surface receptor using the complexes and polypeptide described herein.

## Claims

### Claim 1

A hexameric antigen binding complex having agonist activity comprising six subunits, wherein each subunit comprises at least one antigen binding polypeptide comprising at least one antigen binding region from an antibody that binds to OX40 and a modified human IgG1 Fc region that comprises amino acid substitutions E345R, E430G and S440Y, positions according to EU numbering based on native human IgG1, wherein the complex has agonist activity for OX40 bound by the complex.

### Claim 2 (depends on 1)

The complex according to claim 1, wherein each antigen binding polypeptide binds to the same epitope on OX40.

### Claim 3 (depends on 1)

The complex according to claim 1, wherein the antigen binding region is selected from the group consisting of Fv, Fab, Fab′, F(ab′)2 and scFv.

### Claim 4 (depends on 1)

The complex according to claim 1, wherein the Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC).

### Claim 5 (depends on 4)

The complex according to claim 4, wherein the modification for diminished C1q binding and/or CDC comprises a K322A amino acid substitution in the Fc region of a human IgG1 (EU numbering).

### Claim 6 (depends on 1)

The complex according to claim 1, wherein the antigen binding region comprises an antigen binding region from a monospecific antibody, bispecific antibody or multispecific antibody.

### Claim 7 (depends on 1)

The complex according to claim 1, wherein the complex comprises at least one subunit that comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7.

### Claim 8 (depends on 7)

The complex according to claim 7, wherein each of the six subunits comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7.

### Claim 9 (depends on 1)

The complex according to claim 1, wherein the complex comprises at least one subunit that comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 10 (depends on 9)

The complex according to claim 9, wherein each of the six subunits comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 11 (depends on 1)

The complex according to claim 1, wherein the complex comprises (a) at least a first subunit that binds a first epitope of OX40; and (b) at least a second subunit that binds a second epitope of OX40, wherein the first epitope of OX40 is different from the second epitope of OX40.

### Claim 12 (depends on 11)

The complex according to claim 11, wherein the first subunit comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7; and
wherein the second subunit comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 13 (depends on 1)

The complex according to claim 1, wherein the antibody is a bispecific antibody that comprises (a) at least a first arm that binds a first epitope of OX40 and (b) at least a second arm that binds a second epitope of OX40, wherein the first epitope of OX40 is different from the second epitope of OX40.

### Claim 14 (depends on 13)

The complex according to claim 13, wherein the first arm comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:2, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:3, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:4; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:5, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:6, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:7; and
wherein the second arm comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; and/or (b) a VL domain comprising (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO:37, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO:39, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 15 (depends on 1)

The complex according to claim 1, wherein the Fc region further comprises a modification for attenuating effector function.

### Claim 16 (depends on 15)

The complex according to claim 15, wherein the modification for attenuating effector function does not result in a modification of the glycosylation pattern of the Fc region.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising the complex according to any claim 1 and a pharmaceutically acceptable carrier.