# US 2018/0022813 A1 · Antigen binding complex having agonistic activity and methods of use

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- Number: US 2018/0022813 A1
- Document ID: US20180022813A1
- Status: Published application
- Kind: A1
- Application number: 15/725,208
- Filed: 2017-10-04
- Published: 2018-01-25
- 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/US20180022813A1

## 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 for a cell surface receptor and a modified Fc region that enhances hexamer formation, and wherein the complex has agonist activity for a cell surface receptor bound by the complex.

### Claim 2 (depends on 1)

The complex according to claim 1, wherein each antigen binding polypeptide binds to the same cell surface receptor.

### Claim 3 (depends on 2)

The complex according to claim 2, wherein each antigen binding polypeptide binds to the same epitope on the same cell surface receptor.

### Claim 4 (depends on 2)

The complex according to claim 2, wherein the complex comprises two or more antigen binding polypeptides that bind to different epitopes on the same cell surface receptor.

### Claim 5 (depends on 1, 2, 3, 4)

The complex according to any one of claims 1-4, wherein the cell surface receptor is a member of receptor family selected from the group consisting of tumor necrosis factor receptor (TNFR) superfamily and G-Protein Coupled Receptor (GPCR) superfamily.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The complex according to any one of claims 1-5, wherein the cell surface receptor is selected from the group consisting of OX40, CD137, and Tie2.

### Claim 7 (depends on 1, 2, 3, 4, 5, 6)

The complex according to any one of claims 1-6, wherein the antigen binding polypeptide comprises an antigen binding region of an antibody.

### Claim 8 (depends on 7)

The complex according to claim 7, wherein the antigen binding region of an antibody is selected from the group consisting of Fv, Fab, Fab′, F(ab′)2, single-chain antibody molecules (e.g. scFv), and antibody variable region.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The complex according to any one of claims 1-8, wherein the modified Fc region is a modified human IgG1 Fc region.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The complex according to any one of claims 1-9, wherein the Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC).

### Claim 11 (depends on 10)

The complex according to claim 10, 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 12 (depends on 7, 8, 9, 10, 11)

The complex according to any one of claims 7-11, wherein the antigen binding region comprises an antigen binding region from a monospecific antibody, bispecific antibody or multispecific antibody.

### Claim 13 (depends on 12)

The complex according to claim 12, wherein each antigen binding region is from a monospecific antibody that binds to the same cell surface receptor.

### Claim 14 (depends on 12)

The complex according to claim 12, wherein each antigen binding region is from a monospecific antibody that binds to OX40.

### Claim 15 (depends on 14)

The complex according to claim 14, 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 16 (depends on 15)

The complex according to claim 15, 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 17 (depends on 14)

The complex according to claim 14, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 18 (depends on 17)

The complex according to claim 17, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 19 (depends on 13, 14, 15, 17)

The complex according to any one of claims 13-15 and 17, wherein the complex comprises a mixture of at least two monospecific antibodies that bind to different epitopes on the same cell surface receptor.

### Claim 20 (depends on 19)

The complex according to claim 19, 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 21 (depends on 20)

The complex according to claim 20, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 22 (depends on 7, 8, 9, 10, 11, 12)

The complex according to any one of claims 7-12, wherein the antigen binding region comprises two arms of a bispecific antibody, and wherein each arm of the bispecific antibody binds to a different epitope on the same cell surface receptor.

### Claim 23 (depends on 22)

The complex according to claim 22, wherein the bispecific antibody 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 24 (depends on 23)

The complex according to claim 23, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The complex according to any one of claims 1-24, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247A, P247C, P247D, P247F, P247G, P247H, P247I, P247K, P247L, P247M, P247N, P247R, P247S, P247T, P247V, or P247W;
(ii) I253A, I253D, I253K, I253L, I253M, I253N, I253R, I253S, I253V, I253E, I253Q, or I253T;
(iii) S254E, S254F, S254G, S254H, S254I, S254K, S254L, S254P, S254T, S254V, or S254W;
(iv) H310A, H310G, H310F, H310K, H310L, H310P, H310R, H310T, H310V, H310W, H310N, H310Q, or H310Y;
(v) Q311A, Q311C, Q311E, Q311G, Q311H, Q311F, Q311I, Q311K, Q311L, Q311N, Q311P, Q311R, Q311S, Q311T, Q311W, or Q311Y;
(vi) E345A, E345C, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356G, D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(viii) T359G, T359N, T359P, or T359R;
(ix) E382F, E382K, E382L, E382M, E382P, E382V, E382W, E382D, E382H, E382N, E382Q, E382S, E382T, or E382Y;
(x) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(xi) Q386A, Q386C, Q386D, Q386E, Q386G, Q386H, Q386F, Q386I, Q386K, Q386L, Q386N, Q386P, Q386R, Q386S, Q386T, Q386V, Q386W, or Q386Y;
(xii) E430A, E430C, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434D, N434E, N434G, N434K, N434R, N434S, N434V, N434W, N434H, N434Q, N434T, or N434Y;
(xv) Y436I, Y436K, Y436L, Y436R, Y436S, Y436T, Y436V, Y436W, Y436A, Y436E, Y436F, Y436H, Y436M, Y436N, or Y436Q;
(xvi) Q438C, Q438E, Q438I, Q438K, Q438L, Q438S, Q438T, Q438V, Q438W, Q438Y, Q438A, Q438G, Q438H, Q438N, Q438Q, or Q438R;
(xvii) K439A, K439D, K439E, K439H, K439L, K439P, K439R, K439T, K439Y, K439Q, or K439W;
(xviii) S440A, S440C, S440D, S440E, S440G, S440H, S440F, S440I, S440K, S440L, S440M, S440N, S440P, S440Q, S440R, S440T, S440V, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 26 (depends on 25)

The complex according to claim 25, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247G;
(ii) I253L, I253N, I253V, or I253Q;
(iii) S254L;
(iv) H310P, H310W, or H310Q;
(v) Q311E, Q311L, Q311R, or Q311W;
(vi) E345A, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356R;
(viii) T359R;
(ix) E382K, E382L, E382V, E382D, E382Q, or E382S;
(x) G385D, G385N, G385R, G385E, or G385K;
(xi) Q386K;
(xii) E430A, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434K, N434R, N434W, N434H, or N434Q;
(xv) Y436I, Y436S, Y436T, Y436V, Y436N, or Y436Q;
(xvi) Q438C, Q438L, Q438S, Q438T, or Q438N;
(xvii) K439D, K439E, K439H, K439R, or K439Q;
(xviii) S440D, S440E, S440Q, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 27 (depends on 25)

The complex according to claim 25, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247D, P247F, P247G, P247K, P247R, or P247S;
(ii) I253V;
(iii) S254G, S254I, or S254L;
(iv) Q311I, Q311K, Q311L, Q311P, or Q311W;
(v) E345A, E345C, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345S, E345T, E345V, E345W, or E345Y;
(vi) D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(vii) T359N;
(viii) E382L or E382V;
(ix) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(x) Q386K;
(xi) E430A, E430F, E430H, E430L, E430P, E430R, E430S, E430V, E430W, or E430Y;
(xii) N434W;
(xiii) Y436I; and
(xiv) S440D.

### Claim 28 (depends on 25, 26)

The complex according to claim 25 or 26, wherein the modified Fc region comprises one or more amino acid substitutions selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 29 (depends on 28)

The complex according to claim 28, wherein the modified Fc region comprises a single amino acid substitution selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 30 (depends on 28)

The complex according to claim 28, wherein the modified Fc region comprises a set of amino acid substitutions selected from the group consisting of: (a) E345R and E430G, (b) E345R and S440Y, (c) E430G and S440Y, wherein the substitutions are in the Fc region of a human IgG1 (EU numbering).

### Claim 31 (depends on 28)

The complex according to claim 28, wherein the modified Fc region comprises amino acid substitutions E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The complex according to any one of claims 1-31, wherein the Fc region further comprises a modification for attenuating effector function.

### Claim 33 (depends on 32)

The complex according to claim 32, wherein the modification for attenuating effector function comprises amino acid substitutions at one or more amino acid residues (EU numbering) selected from the group consisting of:
(a) 297 in the Fc region of human IgG1,
(b) 234 and 235 in the Fc region of human IgG1,
(c) 234, 235 and 329 in the Fc region of human IgG1,
(d) 234 and 237 in the Fc region of human IgG2,
(e) 235, 237 and 318 in the Fc region of human IgG4,
(f) 228 and 236 in the Fc region of human IgG4,
(g) 268, 309, 330 and 331 in the Fc region of human IgG2,
(h) 220, 226, 229 and 238 in the Fc region of human IgG1,
(i) 226, 229, 233, 234 and 235 in the Fc region of human IgG1,
(j) 234, 235 and 331 in the Fc region of human IgG1,
(k) 226 and 230 in the Fc region of human IgG1, and
(l) 267 and 328 in the Fc region of human IgG1.

### Claim 34 (depends on 32, 33)

The complex according to claim 32 or 33, wherein the modification for attenuating effector function comprises one or more amino acid substitutions (EU numbering) selected from the group consisting of:
(a) N297A in the Fc region of human IgG1,
(b) L234A and L235A in the Fc region of human IgG1,
(c) L234A, L235A and P329G in the Fc region of human IgG1,
(d) V234A and G237A in the Fc region of human IgG2,
(e) L235A, G237A and E318A in the Fc region of human IgG4,
(f) S228P and L236E in the Fc region of human IgG4,
(g) 118 to 260 in the Fc region of human IgG2 or 261 to 447 in the Fc region of human IgG4,
(h) H268Q, V309L, A330S and A331S in the Fc region of human IgG2,
(j) C220S, C226S, C229S and P238S in the Fc region of human IgG1,
(j) C226S, C229S, E233P, L234V and L235A in the Fc region of human IgG1,
(k) L234F, L235E and P331S in the Fc region of human IgG1,
(l) C226S and P230S in the Fc region of human IgG1, and
(m) S267E and L328F in the Fc region of human IgG1.

### Claim 35 (depends on 32, 33, 34)

The complex according to any one of claims 32-34, wherein the modification for attenuating effector function does not result in a modification of the glycosylation pattern of the Fc region.

### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The complex according to any one of claims 1-35, wherein the complex enhances signal transduction mediated by a cell surface receptor bound by the complex.

### Claim 37

An antigen binding polypeptide comprising an antigen binding region for a cell surface receptor and a modified Fc region, wherein the modified Fc region comprises (i) a modification that enhances hexamer formation of the antigen binding polypeptides, and (ii) a modification that attenuates effector function.

### Claim 38 (depends on 37)

The antigen binding polypeptide according to claim 37, wherein the cell surface receptor is a member of receptor family selected from the group consisting of tumor necrosis factor receptor (TNFR) superfamily and G-Protein Coupled Receptor (GPCR) superfamily.

### Claim 39 (depends on 37, 38)

The antigen binding polypeptide according to claim 37 or 38, wherein the cell surface receptor is selected from the group consisting of OX40, CD137, and Tie2.

### Claim 40 (depends on 37, 38, 39)

The antigen binding polypeptide according to any one of claims 37-39, wherein the antigen binding polypeptide comprises an antigen binding region of an antibody.

### Claim 41 (depends on 40)

The antigen binding polypeptide according to claim 40, wherein the antigen binding region of an antibody is selected from the group consisting of Fv, Fab, Fab′, F(ab′)2, single-chain antibody molecules (e.g. scFv), and antibody variable region.

### Claim 42 (depends on 37, 38, 39, 40, 41)

The antigen binding polypeptide according to any one of claims 37-41, wherein the modified Fc region is a modified human IgG1 Fc region.

### Claim 43 (depends on 37, 38, 39, 40, 41, 42)

The antigen binding polypeptide according to any one of claims 37-42, wherein the Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC).

### Claim 44 (depends on 43)

The antigen binding polypeptide according to claim 43, 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 45 (depends on 40, 41, 42, 43, 44)

The antigen binding polypeptide according to any one of claims 40-44, wherein the antigen binding region comprises an antigen binding region from a monospecific antibody, bispecific antibody or multispecific antibody.

### Claim 46 (depends on 45)

The antigen binding polypeptide according to claim 45, wherein the antigen binding region binds to OX40.

### Claim 47 (depends on 46)

The antigen binding polypeptide according to claim 46, wherein the antigen binding region 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 48 (depends on 46)

The antigen binding polypeptide according to claim 46, wherein the antigen binding region 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 49 (depends on 45)

The antigen binding polypeptide according to claim 45, wherein the antigen binding region comprises two arms of a bispecific antibody, and wherein each arm of the bispecific antibody binds to a different epitope on the same cell surface receptor.

### Claim 50 (depends on 49)

The antigen binding polypeptide according to claim 49, wherein the bispecific antibody 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 51 (depends on 50)

The antigen binding polypeptide according to claim 50, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 52 (depends on 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)

The antigen binding polypeptide according to any one of claims 37-51, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247A, P247C, P247D, P247F, P247G, P247H, P247I, P247K, P247L, P247M, P247N, P247R, P247S, P247T, P247V, or P247W;
(ii) I253A, I253D, I253K, I253L, I253M, I253N, I253R, I253S, I253V, I253E, I253Q, or I253T;
(iii) S254E, S254F, S254G, S254H, S254I, S254K, S254L, S254P, S254T, S254V, or S254W;
(iv) H310A, H310G, H310F, H310K, H310L, H310P, H310R, H310T, H310V, H310W, H310N, H310Q, or H310Y;
(v) Q311A, Q311C, Q311E, Q311G, Q311H, Q311F, Q311I, Q311K, Q311L, Q311N, Q311P, Q311R, Q311S, Q311T, Q311W, or Q311Y;
(vi) E345A, E345C, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356G, D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(viii) T359G, T359N, T359P, or T359R;
(ix) E382F, E382K, E382L, E382M, E382P, E382V, E382W, E382D, E382H, E382N, E382Q, E382S, E382T, or E382Y;
(x) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(xi) Q386A, Q386C, Q386D, Q386E, Q386G, Q386H, Q386F, Q386I, Q386K, Q386L, Q386N, Q386P, Q386R, Q386S, Q386T, Q386V, Q386W, or Q386Y;
(xii) E430A, E430C, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434D, N434E, N434G, N434K, N434R, N434S, N434V, N434W, N434H, N434Q, N434T, or N434Y;
(xv) Y436I, Y436K, Y436L, Y436R, Y436S, Y436T, Y436V, Y436W, Y436A, Y436E, Y436F, Y436H, Y436M, Y436N, or Y436Q;
(xvi) Q438C, Q438E, Q438I, Q438K, Q438L, Q438S, Q438T, Q438V, Q438W, Q438Y, Q438A, Q438G, Q438H, Q438N, Q438Q, or Q438R;
(xvii) K439A, K439D, K439E, K439H, K439L, K439P, K439R, K439T, K439Y, K439Q, or K439W;
(xviii) S440A, S440C, S440D, S440E, S440G, S440H, S440F, S440I, S440K, S440L, S440M, S440N, S440P, S440Q, S440R, S440T, S440V, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 53 (depends on 52)

The antigen binding polypeptide according to claim 52, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247G;
(ii) I253L, I253N, I253V, or I253Q;
(iii) S254L;
(iv) H310P, H310W, or H310Q;
(v) Q311E, Q311L, Q311R, or Q311W;
(vi) E345A, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356R;
(viii) T359R;
(ix) E382K, E382L, E382V, E382D, E382Q, or E382S;
(x) G385D, G385N, G385R, G385E, or G385K;
(xi) Q386K;
(xii) E430A, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434K, N434R, N434W, N434H, or N434Q;
(xv) Y436I, Y436S, Y436T, Y436V, Y436N, or Y436Q;
(xvi) Q438C, Q438L, Q438S, Q438T, or Q438N;
(xvii) K439D, K439E, K439H, K439R, or K439Q;
(xviii) S440D, S440E, S440Q, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 54 (depends on 52)

The antigen binding polypeptide according to claim 52, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247D, P247F, P247G, P247K, P247R, or P247S;
(ii) I253V;
(iii) S254G, S254I, or S254L;
(iv) Q311I, Q311K, Q311L, Q311P, or Q311W;
(v) E345A, E345C, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345S, E345T, E345V, E345W, or E345Y;
(vi) D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(vii) T359N;
(viii) E382L or E382V;
(ix) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(x) Q386K;
(xi) E430A, E430F, E430H, E430L, E430P, E430R, E430S, E430V, E430W, or E430Y;
(xii) N434W;
(xiii) Y436I; and
(xiv) S440D.

### Claim 55 (depends on 52, 53)

The antigen binding polypeptide according to claim 52 or 53, wherein the modified Fc region comprises one or more amino acid substitutions selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 56 (depends on 55)

The antigen binding polypeptide according to claim 55, wherein the modified Fc region comprises a single amino acid substitution selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 57 (depends on 55)

The antigen binding polypeptide according to claim 55, wherein the modified Fc region comprises a set of amino acid substitutions selected from the group consisting of: (a) E345R and E430G, (b) E345R and S440Y, (c) E430G and S440Y, wherein the substitutions are in the Fc region of a human IgG1 (EU numbering).

### Claim 58 (depends on 55)

The antigen binding polypeptide according to claim 55, wherein the modified Fc region comprises amino acid substitutions E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 59 (depends on 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The antigen binding polypeptide according to any one of claims 37-58, wherein the modification for attenuating effector function comprises amino acid substitutions at one or more amino acid residues (EU numbering) selected from the group consisting of:
(a) 297 in the Fc region of human IgG1,
(b) 234 and 235 in the Fc region of human IgG1,
(c) 234, 235 and 329 in the Fc region of human IgG1,
(d) 234 and 237 in the Fc region of human IgG2,
(e) 235, 237 and 318 in the Fc region of human IgG4,
(f) 228 and 236 in the Fc region of human IgG4,
(g) 268, 309, 330 and 331 in the Fc region of human IgG2,
(h) 220, 226, 229 and 238 in the Fc region of human IgG1,
(i) 226, 229, 233, 234 and 235 in the Fc region of human IgG1,
(j) 234, 235 and 331 in the Fc region of human IgG1 (EU numbering),
(k) 226 and 230 in the Fc region of human IgG1, and
(l) 267 and 328 in the Fc region of human IgG1.

### Claim 60 (depends on 59)

The antigen binding polypeptide according to claim 59, wherein the modification for attenuating effector function comprises one or more amino acid substitutions (EU numbering) selected from the group consisting of:
(a) N297A in the Fc region of human IgG1,
(b) L234A and L235A in the Fc region of human IgG1,
(c) L234A, L235A and P329G in the Fc region of human IgG1,
(d) V234A and G237A in the Fc region of human IgG2,
(e) L235A, G237A and E318A in the Fc region of human IgG4,
(f) S228P and L236E in the Fc region of human IgG4,
(g) 118 to 260 in the Fc region of human IgG2 or 261 to 447 in the Fc region of human IgG4,
(h) H268Q, V309L, A330S and A331S in the Fc region of human IgG2,
(j) C220S, C226S, C229S and P238S in the Fc region of human IgG1,
(j) C226S, C229S, E233P, L234V and L235A in the Fc region of human,
(k) L234F, L235E and P331S in the Fc region of human IgG1,
(l) C226S and P230S in the Fc region of human IgG1, and
(m) S267E and L328F in the Fc region of human IgG1.

### Claim 61 (depends on 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60)

The antigen binding polypeptide according to any one of claims 37-60, wherein the modification for attenuating effector function does not result in a modification of the glycosylation pattern of the Fc region.

### Claim 62

An antigen binding polypeptide comprising an antigen binding region for a cell surface receptor and a modified Fc region, wherein the modified Fc region comprises a modification that enhances intermolecular interactions between Fc domains upon binding to the cell surface receptor.

### Claim 63 (depends on 62)

The antigen binding polypeptide according to claim 62, wherein the polypeptide enhances receptor agonism upon binding to the cell surface receptor as compared to the same antigen binding polypeptide not having the Fc region modification.

### Claim 64 (depends on 62, 63)

The antigen binding polypeptide according to claim 62 or 63, wherein the cell surface receptor is a member of receptor family selected from the group consisting of tumor necrosis factor receptor (TNFR) superfamily and G-Protein Coupled Receptor (GPCR) superfamily.

### Claim 65 (depends on 62, 63, 64)

The antigen binding polypeptide according to any one of claims 62-64, wherein the cell surface receptor is selected from the group consisting of OX40, CD137, and Tie2.

### Claim 66 (depends on 62, 63, 64, 65)

The antigen binding polypeptide according to any one of claims 62-65, wherein the antigen binding polypeptide comprises an antigen binding region of antibody.

### Claim 67 (depends on 66)

The antigen binding polypeptide according to claim 66, wherein the antigen binding region of an antibody is selected from the group consisting of Fv, Fab, Fab′, F(ab′)2, single-chain antibody molecules (e.g. scFv), and antibody variable region.

### Claim 68 (depends on 62, 63, 64, 65, 66, 67)

The antigen binding polypeptide according to any one of claims 62-67, wherein the modified Fc region is a modified human IgG1 Fc region.

### Claim 69 (depends on 62, 63, 64, 65, 66, 67, 68)

The antigen binding polypeptide according to any one of claims 62-68, wherein the Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC).

### Claim 70 (depends on 69)

The antigen binding polypeptide according to claim 69, 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 71 (depends on 66, 67, 68, 69, 70)

The antigen binding polypeptide according to any one of claims 66-70, wherein the antigen binding region is from a monospecific antibody, bispecific antibody or multispecific antibody.

### Claim 72 (depends on 71)

The antigen binding polypeptide according to claim 71, wherein the antigen binding region binds to OX40.

### Claim 73 (depends on 72)

The antigen binding polypeptide according to claim 72, wherein the antigen binding region 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 74 (depends on 72)

The antigen binding polypeptide according to claim 72, wherein the antigen binding region 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 75 (depends on 71)

The antigen binding polypeptide according to claim 71, wherein the antigen binding region comprises two arms of a bispecific antibody, and wherein each arm of the bispecific antibody binds to a different epitope on the same cell surface receptor.

### Claim 76 (depends on 75)

The antigen binding polypeptide according to claim 75, wherein the bispecific antibody 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 77 (depends on 76)

The antigen binding polypeptide according to claim 76, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 78 (depends on 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77)

The antigen binding polypeptide according to any one of claims 62-77, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247A, P247C, P247D, P247F, P247G, P247H, P247I, P247K, P247L, P247M, P247N, P247R, P247S, P247T, P247V, or P247W;
(ii) I253A, I253D, I253K, I253L, I253M, I253N, I253R, I253S, I253V, I253E, I253Q, or I253T;
(iii) S254E, S254F, S254G, S254H, S254I, S254K, S254L, S254P, S254T, S254V, or S254W;
(iv) H310A, H310G, H310F, H310K, H310L, H310P, H310R, H310T, H310V, H310W, H310N, H310Q, or H310Y;
(v) Q311A, Q311C, Q311E, Q311G, Q311H, Q311F, Q311I, Q311K, Q311L, Q311N, Q311P, Q311R, Q311S, Q311T, Q311W, or Q311Y;
(vi) E345A, E345C, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356G, D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(viii) T359G, T359N, T359P, or T359R;
(ix) E382F, E382K, E382L, E382M, E382P, E382V, E382W, E382D, E382H, E382N, E382Q, E382S, E382T, or E382Y;
(x) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(xi) Q386A, Q386C, Q386D, Q386E, Q386G, Q386H, Q386F, Q386I, Q386K, Q386L, Q386N, Q386P, Q386R, Q386S, Q386T, Q386V, Q386W, or Q386Y;
(xii) E430A, E430C, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434D, N434E, N434G, N434K, N434R, N434S, N434V, N434W, N434H, N434Q, N434T, or N434Y;
(xv) Y436I, Y436K, Y436L, Y436R, Y436S, Y436T, Y436V, Y436W, Y436A, Y436E, Y436F, Y436H, Y436M, Y436N, or Y436Q;
(xvi) Q438C, Q438E, Q438I, Q438K, Q438L, Q438S, Q438T, Q438V, Q438W, Q438Y, Q438A, Q438G, Q438H, Q438N, Q438Q, or Q438R;
(xvii) K439A, K439D, K439E, K439H, K439L, K439P, K439R, K439T, K439Y, K439Q, or K439W;
(xviii) S440A, S440C, S440D, S440E, S440G, S440H, S440F, S440I, S440K, S440L, S440M, S440N, S440P, S440Q, S440R, S440T, S440V, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 79 (depends on 78)

The antigen binding polypeptide according to claim 78, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247G;
(ii) I253L, I253N, I253V, or I253Q;
(iii) S254L;
(iv) H310P, H310W, or H310Q;
(v) Q311E, Q311L, Q311R, or Q311W;
(vi) E345A, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356R;
(viii) T359R;
(ix) E382K, E382L, E382V, E382D, E382Q, or E382S;
(x) G385D, G385N, G385R, G385E, or G385K;
(xi) Q386K;
(xii) E430A, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434K, N434R, N434W, N434H, or N434Q;
(xv) Y436I, Y436S, Y436T, Y436V, Y436N, or Y436Q;
(xvi) Q438C, Q438L, Q438S, Q438T, or Q438N;
(xvii) K439D, K439E, K439H, K439R, or K439Q;
(xviii) S440D, S440E, S440Q, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 80 (depends on 78)

The antigen binding polypeptide according to claim 78, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247D, P247F, P247G, P247K, P247R, or P247S;
(ii) I253V;
(iii) S254G, S254I, or S254L;
(iv) Q311I, Q311K, Q311L, Q311P, or Q311W;
(v) E345A, E345C, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345S, E345T, E345V, E345W, or E345Y;
(vi) D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(vii) T359N;
(viii) E382L or E382V;
(ix) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(x) Q386K;
(xi) E430A, E430F, E430H, E430L, E430P, E430R, E430S, E430V, E430W, or E430Y;
(xii) N434W;
(xiii) Y436I; and
(xiv) S440D.

### Claim 81 (depends on 78, 79)

The antigen binding polypeptide according to claim 78 or 79, wherein the modified Fc region comprises one or more amino acid substitutions selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 82 (depends on 81)

The antigen binding polypeptide according to claim 81, wherein the modified Fc region comprises a single amino acid substitution selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 83 (depends on 81)

The antigen binding polypeptide according to claim 81, wherein the modified Fc region comprises a set of amino acid substitutions selected from the group consisting of: (a) E345R and E430G, (b) E345R and S440Y, (c) E430G and S440Y, wherein the substitutions are in the Fc region of a human IgG1 (EU numbering).

### Claim 84 (depends on 81)

The antigen binding polypeptide according to claim 81, wherein the modified Fc region comprises amino acid substitutions E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 85 (depends on 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84)

The antigen binding polypeptide according to any one of claims 62-84, wherein the modified Fc region further comprises a modification that attenuates effector function.

### Claim 86 (depends on 85)

The antigen binding polypeptide according to claim 85, wherein the modification for attenuating effector function comprises amino acid substitutions at one or more amino acid residues (EU numbering) selected from the group consisting of:
(a) 297 in the Fc region of human IgG1,
(b) 234 and 235 in the Fc region of human IgG1,
(c) 234, 235 and 329 in the Fc region of human IgG1,
(d) 234 and 237 in the Fc region of human IgG2,
(e) 235, 237 and 318 in the Fc region of human IgG4,
(f) 228 and 236 in the Fc region of human IgG4,
(g) 268, 309, 330 and 331 in the Fc region of human IgG2,
(h) 220, 226, 229 and 238 in the Fc region of human IgG1,
(i) 226, 229, 233, 234 and 235 in the Fc region of human IgG1,
(j) 234, 235 and 331 in the Fc region of human IgG1 (EU numbering),
(k) 226 and 230 in the Fc region of human IgG1, and
(l) 267 and 328 in the Fc region of human IgG1.

### Claim 87 (depends on 85, 86)

The antigen binding polypeptide according to claim 85 or 86, wherein the modification for attenuating effector function comprises one or more amino acid substitutions (EU numbering) selected from the group consisting of:
(a) N297A in the Fc region of human IgG1,
(b) L234A and L235A in the Fc region of human IgG1,
(c) L234A, L235A and P329G in the Fc region of human IgG1,
(d) V234A and G237A in the Fc region of human IgG2,
(e) L235A, G237A and E318A in the Fc region of human IgG4,
(f) S228P and L236E in the Fc region of human IgG4,
(g) 118 to 260 in the Fc region of human IgG2 or 261 to 447 in the Fc region of human IgG4,
(h) H268Q, V309L, A330S and A331S in the Fc region of human IgG2,
(j) C220S, C226S, C229S and P238S in the Fc region of human IgG1,
(j) C226S, C229S, E233P, L234V and L235A in the Fc region of human,
(k) L234F, L235E and P331S in the Fc region of human IgG1,
(l) C226S and P230S in the Fc region of human IgG1, and
(m) S267E and L328F in the Fc region of human IgG1.

### Claim 88 (depends on 85, 86, 87)

The antigen binding polypeptide according to any one of claims 85-87, wherein the modification for attenuating effector function does not result in a modification of the glycosylation pattern of the Fc region.

### Claim 89 (depends on 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)

A hexamer comprising six antigen binding polypeptides according to any one of claims 37 to 88.

### Claim 90 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89)

A method for agonizing a cell surface receptor in a subject comprising administering to the subject a complex according to any one of claims 1 to 36, the hexamer of claim 89 or the antigen binding polypeptide according to any one of claims 37 to 88.

### Claim 91 (depends on 90)

The method of claim 90, wherein the hexamer enhances signal transduction mediated by a cell surface receptor bound by the complex, hexamer or antigen binding polypeptide.

### Claim 92

A method of increasing agonist activity of an antigen binding polypeptide, comprising:
(a) providing an antigen binding polypeptide which comprises an antigen binding region for a cell surface receptor and a Fc region, and
(b) introducing a modification into the Fc region, wherein the modification enhances intermolecular interactions between Fc domains upon binding to a cell surface receptor, and wherein the antigen binding polypeptide has increased agonist activity for a cell surface receptor bound by the antigen binding polypeptide as compared to the same antigen binding polypeptide not having the Fc region modification.

### Claim 93

A method of increasing agonist activity of an antigen binding polypeptide, comprising:
(a) providing an antigen binding polypeptide which comprises an antigen binding region for a cell surface receptor and a Fc region, and
(b) introducing a modification into the Fc region, wherein the modification enhances hexamer formation of the antigen binding polypeptide, and wherein the hexamer has increased agonist activity for a cell surface receptor bound by the antigen binding polypeptide as compared to an individual subunit of the hexamer.

### Claim 94 (depends on 92, 93)

The method according to claim 92 or 93, wherein the cell surface receptor is a member of receptor family selected from the group consisting of tumor necrosis factor receptor (TNFR) superfamily and G-Protein Coupled Receptor (GPCR) superfamily.

### Claim 95 (depends on 92, 93, 94)

The method according to any one of claims 92-94, wherein the cell surface receptor is selected from the group consisting of OX40, CD137, and Tie2.

### Claim 96 (depends on 92, 93, 94, 95)

The method according to any one of claims 92-95, wherein the antigen binding polypeptide comprises an antigen binding region of an antibody.

### Claim 97 (depends on 96)

The method according to claim 96, wherein the antigen binding region of an antibody is selected from the group consisting of Fv, Fab, Fab′, F(ab′)2, single-chain antibody molecules (e.g. scFv), and antibody variable region.

### Claim 98 (depends on 92, 93, 94, 95, 96, 97)

The method according to any one of claims 92-97, wherein the modified Fc region is a modified human IgG1 Fc region.

### Claim 99 (depends on 92, 93, 94, 95, 96, 97, 98)

The method according to any one of claims 92-98, wherein the Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC).

### Claim 100 (depends on 99)

The method according to claim 99, 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 101 (depends on 96, 97, 98, 99, 100)

The method according to any one of claims 96-100, wherein the antigen binding region comprises an antigen binding region from a monospecific antibody, bispecific antibody or multispecific antibody.

### Claim 102 (depends on 96, 97, 98, 99, 100, 101)

The method according to any one of claims 96-101, wherein the antigen binding region binds to OX40.

### Claim 103 (depends on 102)

The method according to claim 102, wherein the antigen binding region 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 104 (depends on 102)

The method according to claim 102, wherein the antigen binding region 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 105 (depends on 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104)

The method according to any one of claims 92-104, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247A, P247C, P247D, P247F, P247G, P247H, P247I, P247K, P247L, P247M, P247N, P247R, P247S, P247T, P247V, or P247W;
(ii) I253A, I253D, I253K, I253L, I253M, I253N, I253R, I253S, I253V, I253E, I253Q, or I253T;
(iii) S254E, S254F, S254G, S254H, S254I, S254K, S254L, S254P, S254T, S254V, or S254W;
(iv) H310A, H310G, H310F, H310K, H310L, H310P, H310R, H310T, H310V, H310W, H310N, H310Q, or H310Y;
(v) Q311A, Q311C, Q311E, Q311G, Q311H, Q311F, Q311I, Q311K, Q311L, Q311N, Q311P, Q311R, Q311S, Q311T, Q311W, or Q311Y;
(vi) E345A, E345C, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356G, D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(viii) T359G, T359N, T359P, or T359R;
(ix) E382F, E382K, E382L, E382M, E382P, E382V, E382W, E382D, E382H, E382N, E382Q, E382S, E382T, or E382Y;
(x) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(xi) Q386A, Q386C, Q386D, Q386E, Q386G, Q386H, Q386F, Q386I, Q386K, Q386L, Q386N, Q386P, Q386R, Q386S, Q386T, Q386V, Q386W, or Q386Y;
(xii) E430A, E430C, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434D, N434E, N434G, N434K, N434R, N434S, N434V, N434W, N434H, N434Q, N434T, or N434Y;
(xv) Y436I, Y436K, Y436L, Y436R, Y436S, Y436T, Y436V, Y436W, Y436A, Y436E, Y436F, Y436H, Y436M, Y436N, or Y436Q;
(xvi) Q438C, Q438E, Q438I, Q438K, Q438L, Q438S, Q438T, Q438V, Q438W, Q438Y, Q438A, Q438G, Q438H, Q438N, Q438Q, or Q438R;
(xvii) K439A, K439D, K439E, K439H, K439L, K439P, K439R, K439T, K439Y, K439Q, or K439W;
(xviii) S440A, S440C, S440D, S440E, S440G, S440H, S440F, S440I, S440K, S440L, S440M, S440N, S440P, S440Q, S440R, S440T, S440V, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 106 (depends on 105)

The method according to claim 105, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247G;
(ii) I253L, I253N, I253V, or I253Q;
(iii) S254L;
(iv) H310P, H310W, or H310Q;
(v) Q311E, Q311L, Q311R, or Q311W;
(vi) E345A, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356R;
(viii) T359R;
(ix) E382K, E382L, E382V, E382D, E382Q, or E382S;
(x) G385D, G385N, G385R, G385E, or G385K;
(xi) Q386K;
(xii) E430A, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434K, N434R, N434W, N434H, or N434Q;
(xv) Y436I, Y436S, Y436T, Y436V, Y436N, or Y436Q;
(xvi) Q438C, Q438L, Q438S, Q438T, or Q438N;
(xvii) K439D, K439E, K439H, K439R, or K439Q;
(xviii) S440D, S440E, S440Q, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 107 (depends on 105)

The method according to claim 105, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247D, P247F, P247G, P247K, P247R, or P247S;
(ii) I253V;
(iii) S254G, S254I, or S254L;
(iv) Q311I, Q311K, Q311L, Q311P, or Q311W;
(v) E345A, E345C, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345S, E345T, E345V, E345W, or E345Y;
(vi) D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(vii) T359N;
(viii) E382L or E382V;
(ix) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(x) Q386K;
(xi) E430A, E430F, E430H, E430L, E430P, E430R, E430S, E430V, E430W, or E430Y;
(xii) N434W;
(xiii) Y436I; and
(xiv) S440D.

### Claim 108 (depends on 105, 106)

The method according to claim 105 or 106, wherein the modified Fc region comprises one or more amino acid substitutions selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 109 (depends on 108)

The method according to claim 108, wherein the modified Fc region comprises a single amino acid substitution selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 110 (depends on 108)

The method according to claim 108, wherein the modified Fc region comprises a set of amino acid substitutions selected from the group consisting of: (a) E345R and E430G, (b) E345R and S440Y, (c) E430G and S440Y, wherein the substitutions are in the Fc region of a human IgG1 (EU numbering).

### Claim 111 (depends on 108)

The method according to claim 108, wherein the modified Fc region comprises amino acid substitutions E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 112 (depends on 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111)

The method according to any one of claims 92-111, wherein the Fc region further comprises a modification for attenuating effector function.

### Claim 113 (depends on 112)

The method according to claim 112, wherein the modification for attenuating effector function comprises amino acid substitutions at one or more amino acid residues (EU numbering) selected from the group consisting of:
(a) 297 in the Fc region of human IgG1,
(b) 234 and 235 in the Fc region of human IgG1,
(c) 234, 235 and 329 in the Fc region of human IgG1,
(d) 234 and 237 in the Fc region of human IgG2,
(e) 235, 237 and 318 in the Fc region of human IgG4,
(f) 228 and 236 in the Fc region of human IgG4,
(g) 268, 309, 330 and 331 in the Fc region of human IgG2,
(h) 220, 226, 229 and 238 in the Fc region of human IgG1,
(i) 226, 229, 233, 234 and 235 in the Fc region of human IgG1,
(j) 234, 235 and 331 in the Fc region of human IgG1,
(k) 226 and 230 in the Fc region of human IgG1, and
(l) 267 and 328 in the Fc region of human IgG1.

### Claim 114 (depends on 112, 113)

The method according to claim 112 or 113, wherein the modification for attenuating effector function comprises one or more amino acid substitutions (EU numbering) selected from the group consisting of:
(a) N297A in the Fc region of human IgG1,
(b) L234A and L235A in the Fc region of human IgG1,
(c) L234A, L235A and P329G in the Fc region of human IgG1,
(d) V234A and G237A in the Fc region of human IgG2,
(e) L235A, G237A and E318A in the Fc region of human IgG4,
(f) S228P and L236E in the Fc region of human IgG4,
(g) 118 to 260 in the Fc region of human IgG2 or 261 to 447 in the Fc region of human IgG4,
(h) H268Q, V309L, A330S and A331S in the Fc region of human IgG2,
(j) C220S, C226S, C229S and P238S in the Fc region of human IgG1,
(j) C226S, C229S, E233P, L234V and L235A in the Fc region of human IgG1,
(k) L234F, L235E and P331S in the Fc region of human IgG1,
(l) C226S and P230S in the Fc region of human IgG1, and
(m) S267E and L328F in the Fc region of human IgG1.

### Claim 115 (depends on 112, 113, 114)

The method according to any one of claims 112-114, wherein the modification for attenuating effector function does not result in a modification of the glycosylation pattern of the Fc region.

### Claim 116 (depends on 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115)

The method according to any one of claims 93-115, wherein the hexamer enhances signal transduction mediated by a cell surface receptor bound by the hexamer.

### Claim 117

A method of identifying an antigen binding polypeptide having agonist activity for a cell surface receptor, comprising:
(a) providing a plurality of antigen binding polypeptides, wherein each antigen binding polypeptide comprising at least one antigen binding region and a modified Fc region that enhances intermolecular interactions between Fc domains upon binding to the cell surface receptor,
(b) screening the antigen binding complexes against a cell surface receptor, and
(c) selecting antigen binding complexes having agonist activity for the cell surface receptor.

### Claim 118

A method of identifying an antigen binding polypeptide having agonist activity for a cell surface receptor, comprising:
(a) providing a plurality of hexameric antigen binding complexes, wherein each complex comprises six subunits each comprising an antigen binding polypeptide comprising at least one antigen binding region and a modified Fc region that enhances hexamer formation,
(b) screening the antigen binding complexes against a cell surface receptor, and
(c) selecting antigen binding complexes having agonist activity for the cell surface receptor.

### Claim 119 (depends on 117, 118)

The method according to claim 117 or 118, wherein the Fc region further comprises a modification that attenuates effector function.

### Claim 120 (depends on 117, 118, 119)

The method according to any one of claims 117-119, wherein the Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC).

### Claim 121

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 for a cell surface receptor and a modified Fc region that enhances hexamer formation, wherein the modified Fc region further comprises a modification for diminished C1q binding and/or Complement Dependent Cytotoxicity (CDC), and wherein the complex has agonist activity for a cell surface receptor bound by the complex.

### Claim 122 (depends on 121)

The complex according to claim 121, wherein each antigen binding polypeptide binds to the same cell surface receptor.

### Claim 123 (depends on 122)

The complex according to claim 122, wherein each antigen binding polypeptide binds to the same epitope on the same cell surface receptor.

### Claim 124 (depends on 122)

The complex according to claim 122, wherein the complex comprises two or more antigen binding polypeptides that bind to different epitopes on the same cell surface receptor.

### Claim 125 (depends on 121, 122, 123, 124)

The complex according to any one of claims 121-124, wherein the cell surface receptor is a member of receptor family selected from the group consisting of tumor necrosis factor receptor (TNFR) superfamily and G-Protein Coupled Receptor (GPCR) superfamily.

### Claim 126 (depends on 121, 122, 123, 124, 125)

The complex according to any one of claims 121-125, wherein the cell surface receptor is selected from the group consisting of OX40, CD137, and Tie2.

### Claim 127 (depends on 121, 122, 123, 124, 125, 126)

The complex according to any one of claims 121-126, wherein the antigen binding polypeptide comprises an antigen binding region of an antibody.

### Claim 128 (depends on 127)

The complex according to claim 127, wherein the antigen binding region of an antibody is selected from the group consisting of Fv, Fab, Fab′, F(ab′)2, single-chain antibody molecules (e.g. scFv), and antibody variable region.

### Claim 129 (depends on 121, 122, 123, 124, 125, 126, 127, 128)

The complex according to any one of claims 121-128, wherein the modified Fc region is a modified human IgG1 Fc region.

### Claim 130 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129)

The complex according to any one of claims 121-129, 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 131 (depends on 127, 128, 129, 130)

The complex according to any one of claims 127-130, wherein the antigen binding region comprises an antigen binding region from a monospecific antibody, bispecific antibody or multispecific antibody.

### Claim 132 (depends on 131)

The complex according to claim 131, wherein each antigen binding region is from a monospecific antibody that binds to the same cell surface receptor.

### Claim 133 (depends on 131)

The complex according to claim 131, wherein each antigen binding region is from a monospecific antibody that binds to OX40.

### Claim 134 (depends on 133)

The complex according to claim 133, 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 135 (depends on 134)

The complex according to claim 134, 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 136 (depends on 133)

The complex according to claim 133, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 137 (depends on 136)

The complex according to claim 136, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 138 (depends on 132, 133, 134, 136)

The complex according to any one of claims 132-134 and 136, wherein the complex comprises a mixture of at least two monospecific antibodies that bind to different epitopes on the same cell surface receptor.

### Claim 139 (depends on 138)

The complex according to claim 138, 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 140 (depends on 139)

The complex according to claim 139, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 141 (depends on 127, 128, 129, 130, 131)

The complex according to any one of claims 127-131, wherein the antigen binding region comprises two arms of a bispecific antibody, and wherein each arm of the bispecific antibody binds to a different epitope on the same cell surface receptor.

### Claim 142 (depends on 141)

The complex according to claim 141, wherein the bispecific antibody 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 143 (depends on 142)

The complex according to claim 142, 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:38, and (iii) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO:42.

### Claim 144 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143)

The complex according to any one of claims 121-143, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247A, P247C, P247D, P247F, P247G, P247H, P247I, P247K, P247L, P247M, P247N, P247R, P247S, P247T, P247V, or P247W;
(ii) I253A, I253D, I253K, I253L, I253M, I253N, I253R, I253S, I253V, I253E, I253Q, or I253T;
(iii) S254E, S254F, S254G, S254H, S254I, S254K, S254L, S254P, S254T, S254V, or S254W;
(iv) H310A, H310G, H310F, H310K, H310L, H310P, H310R, H310T, H310V, H310W, H310N, H310Q, or H310Y;
(v) Q311A, Q311C, Q311E, Q311G, Q311H, Q311F, Q311I, Q311K, Q311L, Q311N, Q311P, Q311R, Q311S, Q311T, Q311W, or Q311Y;
(vi) E345A, E345C, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356G, D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(viii) T359G, T359N, T359P, or T359R;
(ix) E382F, E382K, E382L, E382M, E382P, E382V, E382W, E382D, E382H, E382N, E382Q, E382S, E382T, or E382Y;
(x) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(xi) Q386A, Q386C, Q386D, Q386E, Q386G, Q386H, Q386F, Q386I, Q386K, Q386L, Q386N, Q386P, Q386R, Q386S, Q386T, Q386V, Q386W, or Q386Y;
(xii) E430A, E430C, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434D, N434E, N434G, N434K, N434R, N434S, N434V, N434W, N434H, N434Q, N434T, or N434Y;
(xv) Y436I, Y436K, Y436L, Y436R, Y436S, Y436T, Y436V, Y436W, Y436A, Y436E, Y436F, Y436H, Y436M, Y436N, or Y436Q;
(xvi) Q438C, Q438E, Q438I, Q438K, Q438L, Q438S, Q438T, Q438V, Q438W, Q438Y, Q438A, Q438G, Q438H, Q438N, Q438Q, or Q438R;
(xvii) K439A, K439D, K439E, K439H, K439L, K439P, K439R, K439T, K439Y, K439Q, or K439W;
(xviii) S440A, S440C, S440D, S440E, S440G, S440H, S440F, S440I, S440K, S440L, S440M, S440N, S440P, S440Q, S440R, S440T, S440V, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 145 (depends on 144)

The complex according to claim 144, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247G;
(ii) I253L, I253N, I253V, or I253Q;
(iii) S254L;
(iv) H310P, H310W, or H310Q;
(v) Q311E, Q311L, Q311R, or Q311W;
(vi) E345A, E345D, E345G, E345H, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345Q, E345R, E345S, E345T, E345V, E345W, or E345Y;
(vii) D/E356R;
(viii) T359R;
(ix) E382K, E382L, E382V, E382D, E382Q, or E382S;
(x) G385D, G385N, G385R, G385E, or G385K;
(xi) Q386K;
(xii) E430A, E430D, E430F, E430G, E430H, E430I, E430K, E430L, E430M, E430N, E430P, E430Q, E430R, E430S, E430T, E430V, E430W, or E430Y;
(xiii) H433R;
(xiv) N434K, N434R, N434W, N434H, or N434Q;
(xv) Y436I, Y436S, Y436T, Y436V, Y436N, or Y436Q;
(xvi) Q438C, Q438L, Q438S, Q438T, or Q438N;
(xvii) K439D, K439E, K439H, K439R, or K439Q;
(xviii) S440D, S440E, S440Q, S440W, or S440Y; and
(xix) K447D, K447E, K447N, K447Q, or a deletion of K447.

### Claim 146 (depends on 144)

The complex according to claim 144, wherein the modified Fc region comprises one or more amino acid modifications selected from the group consisting of:
(i) P247D, P247F, P247G, P247K, P247R, or P247S;
(ii) I253V;
(iii) S254G, S254I, or S254L;
(iv) Q311I, Q311K, Q311L, Q311P, or Q311W;
(v) E345A, E345C, E345F, E345I, E345K, E345L, E345M, E345N, E345P, E345S, E345T, E345V, E345W, or E345Y;
(vi) D/E356I, D/E356L, D/E356R, D/E356T, or D/E356V;
(vii) T359N;
(viii) E382L or E382V;
(ix) G385A, G385D, G385H, G385I, G385L, G385N, G385P, G385Q, G385R, G385S, G385T, G385V, G385E, G385K, G385W, or G385Y;
(x) Q386K;
(xi) E430A, E430F, E430H, E430L, E430P, E430R, E430S, E430V, E430W, or E430Y;
(xii) N434W;
(xiii) Y436I; and
(xiv) S440D.

### Claim 147 (depends on 144, 145)

The complex according to claim 144 or 145, wherein the modified Fc region comprises one or more amino acid substitutions selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 148 (depends on 147)

The complex according to claim 147, wherein the modified Fc region comprises a single amino acid substitution selected from the group consisting of: E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 149 (depends on 147)

The complex according to claim 147, wherein the modified Fc region comprises a set of amino acid substitutions selected from the group consisting of: (a) E345R and E430G, (b) E345R and S440Y, (c) E430G and S440Y, wherein the substitutions are in the Fc region of a human IgG1 (EU numbering).

### Claim 150 (depends on 147)

The complex according to claim 147, wherein the modified Fc region comprises amino acid substitutions E345R, E430G and S440Y in the Fc region of a human IgG1 (EU numbering).

### Claim 151 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150)

The complex according to any one of claims 121-150, wherein the Fc region further comprises a modification for attenuating effector function.

### Claim 152 (depends on 151)

The complex according to claim 151, wherein the modification for attenuating effector function comprises amino acid substitutions at one or more amino acid residues (EU numbering) selected from the group consisting of:
(a) 297 in the Fc region of human IgG1,
(b) 234 and 235 in the Fc region of human IgG1,
(c) 234, 235 and 329 in the Fc region of human IgG1,
(d) 234 and 237 in the Fc region of human IgG2,
(e) 235, 237 and 318 in the Fc region of human IgG4,
(f) 228 and 236 in the Fc region of human IgG4,
(g) 268, 309, 330 and 331 in the Fc region of human IgG2,
(h) 220, 226, 229 and 238 in the Fc region of human IgG1,
(i) 226, 229, 233, 234 and 235 in the Fc region of human IgG1,
(j) 234, 235 and 331 in the Fc region of human IgG1,
(k) 226 and 230 in the Fc region of human IgG1, and
(l) 267 and 328 in the Fc region of human IgG1.

### Claim 153 (depends on 151, 152)

The complex according to claim 151 or 152, wherein the modification for attenuating effector function comprises one or more amino acid substitutions (EU numbering) selected from the group consisting of:
(a) N297A in the Fc region of human IgG1,
(b) L234A and L235A in the Fc region of human IgG1,
(c) L234A, L235A and P329G in the Fc region of human IgG1,
(d) V234A and G237A in the Fc region of human IgG2,
(e) L235A, G237A and E318A in the Fc region of human IgG4,
(f) S228P and L236E in the Fc region of human IgG4,
(g) 118 to 260 in the Fc region of human IgG2 or 261 to 447 in the Fc region of human IgG4,
(h) H268Q, V309L, A330S and A331S in the Fc region of human IgG2,
(j) C220S, C226S, C229S and P238S in the Fc region of human IgG1,
(j) C226S, C229S, E233P, L234V and L235A in the Fc region of human IgG1,
(k) L234F, L235E and P331S in the Fc region of human IgG1,
(l) C226S and P230S in the Fc region of human IgG1, and
(m) S267E and L328F in the Fc region of human IgG1.

### Claim 154 (depends on 151, 152, 153)

The complex according to any one of claims 151-153, wherein the modification for attenuating effector function does not result in a modification of the glycosylation pattern of the Fc region.

### Claim 155 (depends on 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154)

The complex according to any one of claims 121-154, wherein the complex enhances signal transduction mediated by a cell surface receptor bound by the complex.

### Claim 156 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155)

A nucleic acid encoding the complex according to any one of claims 1 to 36 or 121 to 155, the hexamer of claim 89, or the antigen binding polypeptide according to any one of claims 37 to 88.

### Claim 157 (depends on 156)

A vector comprising the nucleic acid of claim 156.

### Claim 158 (depends on 157)

The vector of claim 157, wherein the vector is an expression vector.

### Claim 159 (depends on 157, 158)

A host cell comprising the vector of claim 157 or 158.

### Claim 160 (depends on 159)

The host cell of claim 159, wherein the host cell is prokaryotic.

### Claim 161 (depends on 159)

The host cell of claim 159, wherein the host cell is eukaryotic.

### Claim 162 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 159, 160, 161)

A method for making an antigen binding polypeptide having agonist activity comprising culturing the host cell of any one of claims 159-161 under conditions suitable for expression of the nucleic acid encoding the complex according to any one of claims 1 to 36 or 121 to 155, the hexamer of claim 89, or the antigen binding polypeptide according to any one of claims 37 to 88.

### Claim 163 (depends on 162)

The method of claim 162, further comprising recovering the complex, hexamer or polypeptide from the host cell.

### Claim 164 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155)

A pharmaceutical composition comprising the complex according to any one of claims 1 to 36 or 121 to 155, the hexamer of claim 89, or the antigen binding polypeptide according to any one of claims 37 to 88 and a pharmaceutically acceptable carrier.