# US 10,501,552 B2 · Multivalent molecules comprising DR5-binding domains

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- Number: US 10,501,552 B2
- Document ID: US10501552B2
- Status: Granted
- Kind: B2
- Application number: 15/545,871
- Filed: 2015-05-29
- Published: 2018-01-18
- Granted: 2019-12-10
- Earliest claimed: 2015-01-26
- Assignees: MacroGenics, Inc.
- Applicants: MacroGenics, Inc.
- Inventors: Paul A. Moore; Leslie S. Johnson; Jonathan C. Li; Kalpana Shah
- Web page: https://patentgrep.com/patent/US10501552B2

## CPC

- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07K 16/30: from tumour cells
- A61K 2039/505: {comprising antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/35: Valency
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention is directed to multivalent DR5-Binding Molecules that comprise Binding Domain(s) of anti-DR5 antibodies, and particularly Binding Domain(s) of anti-human DR5 antibodies. The DR5-Binding Molecules of the present invention include bivalent and tetravalent molecules having two, three or four DR5-Binding Domains each capable of binding human DR5. In particular, the present invention is directed to multivalent DR5-Binding Molecules that comprise diabodies, and more particularly, diabodies that comprise a covalently bonded complex of two or more polypeptide chains. The invention particularly pertains to such multivalent DR5-Binding Molecules that comprise of the anti-DR5 antibodies DR5 mAb 1 and/or DR5 mAb 2, and/or humanized and chimeric versions of such antibodies.

## Claims

### Claim 1

A multivalent DR5-Binding Molecule that is a monospecific binding molecule, capable of binding to an epitope of human DR5, wherein said multivalent DR5-Binding Molecule comprises four antigen-binding domains each capable of binding human DR5, and wherein each of said antigen-binding domains comprise three Light Chain CDR Domains (CDRL1, CDRL2 and CDRL3) and three Heavy Chain CDR Domains (CDRH1, CDRH2 and CDRH3) wherein:
(i) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11; or
(ii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; or
(iii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of hDR5 mAb 2 VL-3, and, respectively comprise the amino acid sequences: SEQ ID NO:165, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of hDR5 mAb 2 VH-3, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 2

A multivalent DR5-binding molecule having a VL Domain comprising a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, and a VH Domain comprising a CDRH1 Domain, a CDRH2 Domain and a CDRH3 Domain, wherein:
(i) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11; or
(ii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; or
(iii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of hDR5 mAb 2 VL-3, and, respectively comprise the amino acid sequences: SEQ ID NO: 165, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of hDR5 mAb 2 VH-3, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 3 (depends on 2)

A composition comprising the multivalent DR5-Binding Molecule of claim 2 and an excipient.

### Claim 4 (depends on 2)

The multivalent DR5-Binding Molecule of claim 2, wherein said multivalent DR5-Binding Molecule is an Fc Region-containing diabody, said diabody being a covalently bonded complex that comprises two pairs of polypeptides, wherein each pair comprises a first polypeptide chain and a second polypeptide chain.

### Claim 5 (depends on 4)

The multivalent DR5-Binding Molecule of claim 4, wherein said Fc Region comprises one or more amino acid modifications that reduce the affinity of the variant Fc Region for an FcγR or stabilizes said Fc Region.

### Claim 6 (depends on 5)

The multivalent DR5-Binding Molecule of claim 5, wherein said modifications comprise the substitution of L234A; L235A; or L234A and L235A, wherein said numbering is that of the EU index as in Kabat.

### Claim 7

A multivalent DR5-Binding Molecule that is a bispecific binding molecule, capable of simultaneously binding to two different epitopes of human Death Receptor 5 (DR5), wherein said multivalent DR5-Binding Molecule comprises four antigen-binding domains each capable of binding human DR5, and wherein at least one of said antigen-binding domains comprises three Light Chain CDR Domains (CDRL1, CDRL2 and CDRL3) and three Heavy Chain CDR Domains (CDRH1, CDRH2 and CDRH3) wherein:
(i) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11; or
(ii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; or
(iii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain are the Light Chain CDRs of hDR5 mAb 2 VL-3, and, respectively comprise the amino acid sequences: SEQ ID NO:165, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain are the Heavy Chain CDRs of hDR5 mAb 2 VH-3, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 8 (depends on 1)

The multivalent DR5-Binding Molecule of claim 1, wherein said multivalent DR5-Binding Molecule is capable of simultaneously binding to two, three, or four human DR5 polypeptides.

### Claim 9 (depends on 1)

The multivalent DR5-Binding Molecule of claim 1, wherein said multivalent DR5-Binding Molecule is an Fc Region-containing diabody, said diabody being a covalently bonded complex that comprises two pairs of polypeptides, wherein each pair comprises a first polypeptide chain and a second polypeptide chain.

### Claim 10 (depends on 9)

The multivalent DR5-Binding Molecule of claim 9, wherein:
(A) the first polypeptide chain comprises, in the N-terminal to C-terminal direction:
(i) a variable light chain (VL) Domain of a monoclonal antibody capable of binding to a first DR5 epitope (VL1);
(ii) a first peptide linker (Linker 1);
(iii) a variable heavy chain (VH) Domain of a monoclonal antibody capable of binding to a second DR5 epitope (VH2);
(iv) a second peptide linker (Linker 2);
(v) a Heterodimer-Promoting Domain comprising a E-coil Domain or a K-coil Domain;
(vi) a third peptide linker (Linker 3); and
(vii) a polypeptide portion of an IgG Fc Region having CH2 and CH3 domains of an IgG immunoglobulin Fc Region; and
(B) the second polypeptide chain comprises, in the N-terminal to C-terminal direction:
(i) a VL Domain of a monoclonal antibody capable of binding to said second DR5 epitope (VL2);
(ii) a first peptide linker (Linker 1);
(iii) a VH Domain of a monoclonal antibody capable of binding to said first DR5 epitope (VH1);
(iv) a second peptide linker (Linker 2); and
(v) a Heterodimer-Promoting Domain comprising a E-coil Domain or a K-coil Domain, wherein said Heterodimer-Promoting Domain of said first polypeptide chain and said Heterodimer-Promoting Domain of said second polypeptide chain are not both E-coil Domains or both K-coil Domains;
and wherein:
(a) the VL1 Domain of said first polypeptide chain and the VH1 Domain of said second polypeptide chain form an Antigen-Binding Domain capable of specific binding to a first epitope of DR5;
(b) said VH2 Domain of said first polypeptide chain and said VL2 Domain of said second polypeptide chain form an Antigen-Binding Domain capable of specific binding to a second epitope of DR5; and
(c) the CH2-CH3 portions of the pair of first polypeptide chains form an IgG Fc Region.

### Claim 11 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein said VL2 comprises the CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of DR5 mAb 1, respectively comprising the amino acid sequences of SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said VH2 comprises the CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of DR5 mAb 1, respectively comprising the amino acid sequences of SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, and
wherein said VL1 comprises a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, and said VH1 comprises a CDRH1 Domain, a CDRH2 Domain and a CDRH3 Domain, wherein:
(i) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL1 are the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH1 are the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11; or
(ii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL1 are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH1 are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; or
(iii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL1 are the Light Chain CDRs of hDR5 mAb 2 VL-3, and, respectively comprise the amino acid sequences: SEQ ID NO:165, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH1 are the Heavy Chain CDRs of hDR5 mAb 2 VH-3, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 12 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein said VL2 comprises the CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of DR5 mAb 2 or hDR5 mAb 2 VL-3, respectively comprising the amino acid sequences: SEQ ID NO:14 or 165, SEQ ID NO:15, and SEQ ID NO:16, and said VH2 comprises the CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of DR5 mAb 2, respectively comprising the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21, and
wherein said VL1 comprises a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, and said VH1 comprises a CDRH1 Domain, a CDRH2 Domain and a CDRH3 Domain, wherein:
(i) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL1 are the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH1 are the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11; or
(ii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL1 are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH1 are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; or
(iii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL1 are the Light Chain CDRs of DR5 hmAb 2 VL-3, and, respectively comprise the amino acid sequences: SEQ ID NO: 165, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH1 are the Heavy Chain CDRs of DR5 hmAb 2 VL-3, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 13 (depends on 12)

The multivalent DR5-Binding Molecule of claim 12, wherein:
said VL1 comprises the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said VH1 comprises the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11.

### Claim 14 (depends on 12)

The multivalent DR5-Binding Molecule of claim 12, wherein:
said VL1 comprises the Light Chain CDRs of DR5 mAb 2 or hDR5 mAb2 VL-3, and, respectively have the amino acid sequences: SEQ ID NO:14 or 165, SEQ ID NO:15, and SEQ ID NO:16, and VH1 comprises the Heavy Chain CDRs of DR5 mAb 2, and respectively have the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 15 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein:
(i) said VL1 comprises the amino acid sequence of SEQ ID NO:3, and said VH1 comprises the amino acid sequence of SEQ ID NO:8; or
(ii) said VL1 comprises the amino acid sequence of SEQ ID NO:13, and said VH1 comprises the amino acid sequence of SEQ ID NO:18; or
(iii) said VL1 comprises the amino acid sequence of SEQ ID NO:23, and said VH1 comprises the amino acid sequence of SEQ ID NO:31; or
(iv) said VL1 comprises the amino acid sequence of SEQ ID NO:25, and said VH1 comprises the amino acid sequence of SEQ ID NO:31; or
(v) said VL1 comprises the amino acid sequence of SEQ ID NO:27, and said VH1 comprises the amino acid sequence of SEQ ID NO:31; or
(vi) said VL1 comprises the amino acid sequence of SEQ ID NO:29, and said VH1 comprises the amino acid sequence of SEQ ID NO:31.

### Claim 16 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein:
(i) said VL2 comprises the amino acid sequence of SEQ ID NO:3, and said VH2 comprises the amino acid sequence of SEQ ID NO:8; or
(ii) said VL2 comprises the amino acid sequence of SEQ ID NO:13, and said VH2 comprises the amino acid sequence of SEQ ID NO:18; or
(iii) said VL2 comprises the amino acid sequence of SEQ ID NO:23, and said VH2 comprises the amino acid sequence of SEQ ID NO:31; or
(iv) said VL2 comprises the amino acid sequence of SEQ ID NO:25, and said VH2 comprises the amino acid sequence of SEQ ID NO:31; or
(v) said VL2 comprises the amino acid sequence of SEQ ID NO:27, and said VH2 comprises the amino acid sequence of SEQ ID NO:31; or
(vi) said VL2 comprises the amino acid sequence of SEQ ID NO:29, and said VH2 comprises the amino acid sequence of SEQ ID NO:31.

### Claim 17 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein:
(i) said Linker 1 comprises the amino acid sequence of SEQ ID NO:33,
(ii) said Linker 2 comprises the amino acid sequence of SEQ ID NO:47,
(iii) said E-coil Domain comprises the amino acid sequence of SEQ ID NO:41,
(iv) said K-coil Domain comprises the amino acid sequence of SEQ ID NO:42,
(v) said Linker 3 comprises the amino acid sequence of SEQ ID NO:51, and
(vi) said CH2-CH3 domain comprises the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:102, wherein the C-terminal residue is optionally included.

### Claim 18 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein said Fc Region comprises one or more amino acid modifications that reduce the affinity of the variant Fc Region for an FcγR or stabilizes said Fc Region.

### Claim 19 (depends on 18)

The multivalent DR5-Binding Molecule of claim 18, wherein said modifications comprise the substitution of L234A; L235A; or L234A and L235A, wherein said numbering is that of the EU index as in Kabat.

### Claim 20 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein:
(i) said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:116 or SEQ ID NO:120, and said second polypeptide chain comprises the amino acid sequence of SEQ ID NO:118; or
(ii) said first polypeptide chain comprises the amino acid sequence of SEQ ID NO:122 or SEQ ID NO:126, and said second polypeptide chain comprises the amino acid sequence of SEQ ID NO:124.

### Claim 21 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein said VL1 comprises the CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of DR5 mAb 1, respectively comprising the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said VH1 comprises the CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of DR5 mAb 1, respectively comprising the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11, and wherein said VL2 comprises a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, and said VH2 comprises a CDRH1 Domain, a CDRH2 Domain and a CDRH3 Domain, wherein:
(i) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL2 are the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH2 are the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11; or
(ii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL2 are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH2 are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; or
(iii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL2 are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO: 165, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH2 are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 22 (depends on 10)

The multivalent DR5-Binding Molecule of claim 10, wherein said VL1 comprises the CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of DR5 mAb 2 or hDR5 mAb 2 VL-3, respectively comprising the amino acid sequences: SEQ ID NO:14 or 165, SEQ ID NO:15, and SEQ ID NO:16, and said VH1 comprises the CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of DR5 mAb 2, respectively comprising the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21, and wherein said VL2 comprises a CDRL1 Domain, a CDRL2 Domain, and a CDRL3 Domain, and said VH2 comprises a CDRH1 Domain, a CDRH2 Domain and a CDRH3 Domain, wherein:
(i) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL2 are the Light Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH2 are the Heavy Chain CDRs of DR5 mAb 1, and respectively comprise the amino acid sequences: SEQ ID NO:9, SEQ ID NO:10, and SEQ ID NO:11; or
(ii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL2 are the Light Chain CDRs of DR5 mAb 2, and, respectively comprise the amino acid sequences: SEQ ID NO:14, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH2 are the Heavy Chain CDRs of DR5 mAb 2, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21; or
(iii) said CDRL1 Domain, CDRL2 Domain, and CDRL3 Domain of said VL2 are the Light Chain CDRs of hDR5 mAb 2 VL-3, and, respectively comprise the amino acid sequences: SEQ ID NO:165, SEQ ID NO:15, and SEQ ID NO:16, and said CDRH1 Domain, CDRH2 Domain, and CDRH3 Domain of said VH2 are the Heavy Chain CDRs of hDR5 mAb 2 VH-3, and respectively comprise the amino acid sequences: SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.

### Claim 23 (depends on 1)

A composition comprising the multivalent DR5-Binding Molecule of claim 1 and an excipient.

### Claim 24 (depends on 1)

A method of treating cancer comprising administering to an individual having a cancer a therapeutically effective amount of the multivalent DR5-Binding Molecule of claim 1.

### Claim 25 (depends on 24)

The method of claim 24, wherein said molecule is administered to said patient in combination with a histone deacetylase inhibitor.

### Claim 26 (depends on 24)

The method of claim 24, wherein said cancer is selected from the group consisting of: a breast cancer, a stomach cancer, a pancreatic cancer, a colorectal cancer, a kidney cancer, a lung cancer, an ovarian cancer, a liver cancer, a prostate cancer, and a skin cancer.