# US 2014/0154252 A1 · Single-chain multivalent binding proteins with effector function

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- Number: US 2014/0154252 A1
- Document ID: US20140154252A1
- Status: Published application
- Kind: A1
- Application number: 13/815,724
- Filed: 2013-03-15
- Published: 2014-06-05
- Earliest claimed: 2006-06-12
- Assignees: Emergent Product Development Seattle, LLC
- Applicants: Emergent Product Development Seattle, LLC
- Inventors: PETER ARMSTRONG THOMPSON; JEFFREY A. LEDBETTER; MARTHA SUSAN HAYDEN-LEDBETTER; WILLIAM BRADY
- Web page: https://patentgrep.com/patent/US20140154252A1

## CPC

- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 31/22: for herpes viruses
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/18: against material from animals or humans
- C07K 16/2803: {against the immunoglobulin superfamily}
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2818: {against CD28 or CD152}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- C07K 16/2833: {against MHC-molecules, e.g. HLA-molecules}
- C07K 16/2851: {against the lectin superfamily, e.g. CD23, CD72}
- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- C07K 16/2887: {against CD20}
- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- C07K 16/30: from tumour cells
- C07K 16/46: Hybrid immunoglobulins (hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00)
- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/31: multispecific
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/52: Constant or Fc region; Isotype
- C07K 2317/53: Hinge
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/64: comprising a combination of variable region and constant region components
- C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC]
- C07K 2317/734: Complement-dependent cytotoxicity [CDC]
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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

Variations on the structural themes for multivalent binding molecules with effector function, or scorpions, will be apparent to those of skill in the art upon review of the present disclosure, and such variant structures are within the scope of the invention.

## Claims

### Claim 1

A multivalent binding protein comprising, from amino to carboxyl terminus:
a) a first binding domain;
b) a constant sub-region comprising an immunoglobulin hinge region, CH2 domain and a CH3 domain;
c) a C-terminus linker peptide; and
d) a second binding domain,
wherein the binding protein is capable of cross-linking two or more targets.

### Claim 2 (depends on 1)

The multivalent binding protein of claim 1, wherein at least one of the first binding domain and the second binding domain recognizes a target selected from the group consisting of a tumor antigen, a B-cell target, a TNF receptor superfamily member, a Hedgehog family member, a receptor tyrosine kinase, a proteoglycan-related molecule, a TGF-beta superfamily member, a Wnt-related molecule, a receptor ligand, a T-cell target, a Dendritic cell target, an NK cell target, a monocyte/macrophage cell target and an angiogenesis target.

### Claim 3 (depends on 1)

The multivalent binding protein of claim 1, wherein at least one of the first binding domain and the second binding domain recognizes a tumor antigen.

### Claim 4 (depends on 3)

The multivalent binding protein of claim 3, wherein the tumor antigen is selected from the group consisting of SQUAMOUS CELL CARCINOMA ANTIGEN 1 (SCCA-1), (PROTEIN T4-A), SQUAMOUS CELL CARCINOMA ANTIGEN 2 (SCCA-2), Ovarian carcinoma antigen CA125 (1A1-3B; KIAA0049), MUCIN 1 (TUMOR-ASSOCIATED MUCIN; CARCINOMA-ASSOCIATED MUCIN; POLYMORPHIC EPITHELIAL MUCIN; PEM; PEMT; EPISIALIN; TUMOR-ASSOCIATED EPITHELIAL MEMBRANE ANTIGEN; EMA; H23AG; PEANUT-REACTIVE URINARY MUCIN; PUM; and BREAST CARCINOMA-ASSOCIATED ANTIGEN DF3), CTCL tumor antigen se1-1, CTCL tumor antigen se14-3, CTCL tumor antigen se20-4, CTCL tumor antigen se20-9, CTCL tumor antigen se33-1, CTCL tumor antigen se37-2, CTCL tumor antigen se57-1, CTCL tumor antigen se89-1, Prostate-specific membrane antigen, 5T4 oncofetal trophoblast glycoprotein, Orf73 Kaposi's sarcoma-associated herpesvirus, MAGE-C1 (cancer/testis antigen CT7), MAGE-B1 ANTIGEN (MAGE-XP ANTIGEN; DAM10), MAGE-B2 ANTIGEN (DAM6), MAGE-2 ANTIGEN, MAGE-4a antigen, MAGE-4b antigen, Colon cancer antigen NY-CO-45, Lung cancer antigen NY-LU-12 variant A, Cancer associated surface antigen, Adenocarcinoma antigen ART1, Paraneoplastic associated brain-testis-cancer antigen (onconeuronal antigen MA2; paraneoplastic neuronal antigen), Neuro-oncological ventral antigen 2 (NOVA2), Hepatocellular carcinoma antigen gene 520, TUMOR-ASSOCIATED ANTIGEN CO-029, Tumor-associated antigen MAGE-X2, Synovial sarcoma, X breakpoint 2, Squamous cell carcinoma antigen recognized by T cell, Serologically defined colon cancer antigen 1, Serologically defined breast cancer antigen NY-BR-15, Serologically defined breast cancer antigen NY-BR-16, Chromogranin A, parathyroid secretory protein 1, DUPAN-2, CA 19-9, CA 72-4, CA 195 and L6.

### Claim 5 (depends on 3)

The multivalent binding protein of claim 3, wherein the tumor antigen is prostate-specific membrane antigen.

### Claim 6 (depends on 3)

The multivalent binding protein of claim 3, wherein the tumor antigen is a CTCL tumor antigen.

### Claim 7 (depends on 6)

The multivalent binding protein of claim 6, wherein the CTCL tumor antigen is selected from the group consisting of CTCL tumor antigen se1-1, CTCL tumor antigen se14-3, CTCL tumor antigen se20-9, CTCL tumor antigen se20-4, CTCL tumor antigen se33-1, CTCL tumor antigen se37-2, CTCL tumor antigen se57-1 and CTCL tumor antigen se89-1.

### Claim 8 (depends on 1)

The multivalent binding protein of claim 1, wherein at least one of the first binding domain and the second binding domain recognizes a B cell target.

### Claim 9 (depends on 8)

The multivalent binding protein of claim 8, wherein the B cell target is selected from the group consisting of CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD38, CD39, CD40, CD72, CD73, CD74, CDw75, CDw76, CD77, CD78, CD79a/b, CD80, CD81, CD82, CD83, CD84, CD85, CD86, CD89, CD98, CD126, CD127, CDw130, CD138 and CDw150.

### Claim 10 (depends on 9)

The multivalent binding protein of claim 9, wherein the B cell target is CD37.

### Claim 11 (depends on 9)

The multivalent binding protein of claim 9, wherein the B cell target is CD86 or CD80.

### Claim 12 (depends on 1)

The multivalent binding protein of claim 1, wherein at least one of the first binding domain and the second binding domain recognizes a T-cell target.

### Claim 13 (depends on 11)

The multivalent binding protein of claim 11, wherein the T-cell target is selected from the group consisting of 2B4/SLAMF4, IL-2 R alpha, 4-1BB/TNFRSF9, IL-2 R beta, ALCAM, B7-1/CD80, IL-4 R, B7-H3, BLAME/SLAMF8, BTLA, IL-6 R, CCR3, IL-7 R alpha, CCR4, CXCR1/IL-8 RA, CCR5, CCR6, IL-10 R alpha, CCR7, IL-10 R beta, CCR8, IL-12 R beta 1, CCR9, IL-12 R beta 2, CD2, IL-13 R alpha 1, IL-13, CD3, CD4, ILT2/CD85j, ILT3/CD85k, ILT4/CD85d, ILT5/CD85a, Integrin alpha 4/CD49d, CD5, Integrin alpha E/CD103, CD6, Integrin alpha M/CD11b, CD8, Integrin alpha X/CD11c, Integrin beta 2/CD18, KIR/CD158, CD27/TNFRSF7, KIR2DL1, CD28, KIR2DL3, CD30/TNFRSF8, KIR2DL4/CD158d, CD31/PECAM-1, KIR2DS4, CD40 Ligand/TNFSF5, LAG-3, CD43, LAIR1, CD45, LAIR2, CD83, Leukotriene B4 R1, CD84/SLAMF5, NCAM-L1, CD94, NKG2A, CD97, NKG2C, CD229/SLAMF3, NKG2D, CD2F-10/SLAMF9, NT-4, CD69, NTB-A/SLAMF6, Common gamma Chain/IL-2 R gamma, Osteopontin, CRACC/SLAMF7, PD-1, CRTAM, PSGL-1, CTLA-4, RANK/TNFRSF11A, CX3CR1, CX3CL1, L-Selectin, CXCR3, SIRP beta 1, CXCR4, SLAM, CXCR6, TCCR/WSX-1, DNAM-1, Thymopoietin, EMMPRIN/CD147, TIM-1, EphB6, TIM-2, Fas/TNFRSF6, TIM-3, Fas Ligand/TNFSF6, TIM-4, Fc gamma RIII/CD16, TIM-6, GITR/TNFRSF18, TNF R1/TNFRSF1A, Granulysin, TNF R11/TNFRSF1B, HVEM/TNFRSF14, TRAIL R1/TNFRSF10A, ICAM-1/CD54, TRAIL R2/TNFRSF10B, ICAM-2/CD102, TRAIL R3/TNFRSF10C, IFN-gamma R1, TRAIL R4/TNFRSF10D, IFN-gamma R2, TSLP, IL-1 RI and TSLP R.

### Claim 14 (depends on 12)

The multivalent binding protein of claim 12, wherein the T-cell target is CD3.

### Claim 15 (depends on 1)

The multivalent binding protein of claim 1, wherein at least one of the first binding domain and the second binding domain recognizes a NK cell target.

### Claim 16 (depends on 14)

The multivalent binding protein of claim 14, wherein the NK cell target is selected from the group consisting of 2B4/SLAMF4, KIR2DS4, CD155/PVR, KIR3DL1, CD94, LMIR1/CD300A, CD69, LMIR2/CD300c, CRACC/SLAMF7, LMIR3/CD300LF, DNAM-1, LMIR5/CD300LB, Fc epsilon RII, LMIR6/CD300LE, Fc gamma R1/CD64, MICA, Fc gamma RIIB/CD32b, MICB, Fc gamma RIIC/CD32c, MULT-1, Fc gamma RIIA/CD32a, Nectin-2/CD112, Fc gamma RIII/CD16, NKG2A, FcRH1/IRTA5, NKG2C, FcRH2/IRTA4, NKG2D, FcRH4/IRTA1, NKp30, FcRH5/IRTA2, NKp44, Fc Receptor-like 3/CD16-2, NKp46/NCR1, NKp80/KLRF1, NTB-A/SLAMF6, Rae-1, Rae-1 alpha, Rae-1 beta, Rae-1 delta, H60, Rae-1 epsilon, ILT2/CD85j, Rae-1 gamma, ILT3/CD85k, TREM-1, ILT4/CD85d, TREM-2, ILT5/CD85a, TREM-3, KIR/CD158, TREML1/TLT-1, KIR2DL1, ULBP-1, KIR2DL3, ULBP-2, KIR2DL4/CD158d and ULBP-3.

### Claim 17 (depends on 1)

The multivalent binding protein of claim 1, wherein at least one of the first binding domain and the second binding domain recognizes a monocyte/macrophage cell target.

### Claim 18 (depends on 17)

The multivalent binding protein of claim 17, wherein the monocyte/macrophage cell target is selected from the group consisting of B7-1/CD80, ILT4/CD85d, B7-H1, ILT5/CD85a, Common beta Chain, Integrin alpha 4/CD49d, BLAME/SLAMF8, Integrin alpha X/CD11c, CCL6/C10, Integrin beta 2/CD18, CD155/PVR, Integrin beta 3/CD61, CD31/PECAM-1, Latexin, CD36/SR-B3, Leukotriene B4 R1, CD40/TNFRSF5, LIMPII/SR-B2, CD43, LMIR1/CD300A, CD45, LMIR2/CD300c, CD68, LMIR3/CD300LF, CD84/SLAMF5, LMIR5/CD300LB, CD97, LMIR6/CD300LE, CD163, LRP-1, CD2F-10/SLAMF9, MARCO, CRACC/SLAMF7, MD-1, ECF-L, MD-2, EMMPRIN/CD147, MGL2, Endoglin/CD105, Osteoactivin/GPNMB, Fc gamma R1/CD64, Osteopontin, Fc gamma RIIB/CD32b, PD-L2, Fc gamma RIIC/CD32c, Siglec-3/CD33, Fc gamma RIIA/CD32a, SIGNR1/CD209, Fc gamma RIII/CD16, SLAM, GM-CSF R alpha, TCCR/WSX-1, ICAM-2/CD102, TLR3, IFN-gamma R1, TLR4, IFN-gamma R2, TREM-1, IL-1 RII, TREM-2, ILT2/CD85j, TREM-3, ILT3/CD85k, TREML1/TLT-1, 2B4/SLAMF4, IL-10 R alpha, ALCAM, IL-10 R beta, Aminopeptidase N/ANPEP, ILT2/CD85j, Common beta Chain, ILT3/CD85k, C1q R1/CD93, ILT4/CD85d, CCR1, ILT5/CD85a, CCR2, Integrin alpha 4/CD49d, CCR5, Integrin alpha M/CD11b, CCR8, Integrin alpha X/CD11c, CD155/PVR, Integrin beta 2/CD18, CD14, Integrin beta 3/CD61, CD36/SR-B3, LAIR1, CD43, LAIR2, CD45, Leukotriene B4 R1, CD68, LIMPII/SR-B2, CD84/SLAMF5, LMIR1/CD300A, CD97, LMIR2/CD300c, CD163, LMIR3/CD300LF, Coagulation Factor III/Tissue Factor, LMIR5/CD300LB, CX3CR1, CX3CL1, LMIR6/CD300LE, CXCR4, LRP-1, CXCR6, M-CSF R, DEP-1/CD148, MD-1, DNAM-1, MD-2, EMMPRIN/CD147, MMR, Endoglin/CD105, NCAM-L1, Fc gamma R1/CD64, PSGL-1, Fc gamma RIII/CD16, RP105, G-CSF R, L-Selectin, GM-CSF R alpha, Siglec-3/CD33, HVEM/TNFRSF14, SLAM, ICAM-1/CD54, TCCR/WSX-1, ICAM-2/CD102, TREM-1, IL-6 R, TREM-2, CXCR1/IL-8 RA, TREM-3 and TREML1/TLT-1.

### Claim 19 (depends on 1)

The multivalent binding protein of claim 1, wherein at least one of the first binding domain and the second binding domain recognizes a Dendritic cell target.

### Claim 20 (depends on 19)

The multivalent binding protein of claim 19, wherein the Dendritic cell target is selected from the group consisting of CD36/SR-B3, LOX-1/SR-E1, CD68, MARCO, CD163, SR-AI/MSR, CD5L, SREC-I, CL-P1/COLEC12, SREC-II, LIMPII/SR-B2, RP105, TLR4, TLR1, TLR5, TLR2, TLR6, TLR3, TLR9, 4-1BB Ligand/TNFSF9, IL-12/IL-23 p40, 4-Amino-1,8-naphthalimide, ILT2/CD85j, CCL21/6Ckine, ILT3/CD85k, 8-oxo-dG, ILT4/CD85d, 8D6A, ILT5/CD85a, A2B5, Integrin alpha 4/CD49d, Aag, Integrin beta 2/CD18, AMICA, Langerin, B7-2/CD86, Leukotriene B4 R1, B7-H3, LMIR1/CD300A, BLAME/SLAMF8, LMIR2/CD300c, C1q R1/CD93, LMIR3/CD300LF, CCR6, LMIR5/CD300LB, CCR7, LMIR6/CD300LE, CD40/TNFRSF5, MAG/Siglec-4a, CD43, MCAM, CD45, MD-1, CD68, MD-2, CD83, MDL-1/CLEC5A, CD84/SLAMF5, MMR, CD97, NCAM-L1, CD2F-10/SLAMF9, Osteoactivin/GPNMB, Chem 23, PD-L2, CLEC-1, RP105, CLEC-2, Siglec-2/CD22, CRACC/SLAMF7, Siglec-3/CD33, DC-SIGN, Siglec-5, DC-SIGNR/CD299, Siglec-6, DCAR, Siglec-7, DCIR/CLEC4A, Siglec-9, DEC-205, Siglec-10, Dectin-1/CLEC7A, Siglec-F, Dectin-2/CLEC6A, SIGNR1/CD209, DEP-1/CD148, SIGNR4, DLEC, SLAM, EMMPRIN/CD147, TCCR/WSX-1, Fc gamma R1/CD64, TLR3, Fc gamma RIIB/CD32b, TREM-1, Fc gamma RIIC/CD32c, TREM-2, Fc gamma RIIA/CD32a, TREM-3, Fc gamma RIII/CD16, TREML1/TLT-1, ICAM-2/CD102 and Vanilloid R1.

### Claim 21 (depends on 1)

The multivalent binding protein of claim 1, wherein one of the first binding domain and the second binding domain binds a T cell and wherein the other of the first binding domain and the second binding domain binds a cancer cell.

### Claim 22 (depends on 1)

The multivalent binding protein of claim 1, wherein one of the first binding domain and the second binding domain binds a natural killer cell and wherein the other of the first binding domain and the second binding domain binds a cancer cell.

### Claim 23 (depends on 1)

The multivalent binding protein of claim 1, wherein one of the first binding domain and the second binding domain binds a T cell and wherein the other of the first binding domain and the second binding domain binds an infectious agent.

### Claim 24 (depends on 1)

The multivalent binding protein of claim 1, wherein one of the first binding domain and the second binding domain binds a natural killer cell and wherein the other of the first binding domain and the second binding domain binds an infectious agent.

### Claim 25 (depends on 1)

The multivalent binding protein of claim 1, wherein the protein directs cytotoxic T lymphocytes to infectious agents.

### Claim 26 (depends on 1)

The multivalent binding protein of claim 1, wherein the protein directs cytotoxic T lymphocytes to cancer cells.

### Claim 27 (depends on 1)

The multivalent binding protein of claim 1, wherein the protein directs natural killer cells to cancer cells.

### Claim 28 (depends on 1)

The multivalent binding protein of claim 1, wherein the protein directs natural killer cells to infectious agents.

### Claim 29 (depends on 1)

The multivalent binding protein of claim 1, wherein said binding protein does not comprise a CH1 domain.

### Claim 30 (depends on 1)

The multivalent binding protein of claim 1, wherein the hinge is a hinge selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgE, IgA2, synthetic hinge and the hinge-like CH2 domain of IgM.

### Claim 31 (depends on 30)

The multivalent binding protein of claim 30, wherein the hinge is an IgG1 hinge.

### Claim 32 (depends on 31)

The multivalent binding protein of claim 31, wherein the hinge is a human IgG1 hinge with a mutation at one or two cysteine residues.

### Claim 33 (depends on 1)

The multivalent binding protein of claim 1, wherein the first binding domain and the second binding domain are about 20-30 Å apart to about 150-180 Å apart.

### Claim 34 (depends on 1)

The multivalent binding protein of claim 1, wherein the first binding domain and the second binding domain are about 20-30 Å apart to less than about 50 Å apart.

### Claim 35 (depends on 1)

The multivalent binding protein of claim 1, wherein the first binding domain and the second binding domain are about 50 Å apart.

### Claim 36 (depends on 1)

The multivalent binding protein of claim 1, wherein the binding protein exhibits a binding affinity of less than 10−9 M or at least 10−6 M for at least one of the first binding domain and the second binding domain.

### Claim 37 (depends on 1)

The multivalent binding protein of claim 1, wherein the C-terminus linker is derived from the interdomain region of an immunoglobulin superfamily member.

### Claim 38 (depends on 37)

The multivalent binding protein of claim 37, wherein the interdomain region of an immunoglobulin superfamily member comprises an interdomain region between the Ig V-like and Ig C-like regions selected from the group consisting of CD2, CD4, CD22, CD33, CD48, CD58, CD66, CD80, CD86, CD150, CD166 and CD244.

### Claim 39 (depends on 1)

The multivalent binding protein of claim 1, wherein the C-terminus linker comprises an immunoglobulin core hinge region.

### Claim 40 (depends on 1)

The multivalent binding protein of claim 1, wherein the C-terminus linker is derived from a Type II Membrane Protein C-type lectin stalk region.

### Claim 41 (depends on 39)

The multivalent binding protein of claim 39, wherein the C-terminus linker is derived from the stalk region of a type II Membrane Protein C-type lectin selected from the group consisting of CD69, CD72, CD94, NKG2A, and NKG2D.

### Claim 42 (depends on 1)

The multivalent binding protein of claim 1, wherein the C-terminus linker comprises an amino acid sequence selected from the group consisting of SEQ ID NO:111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 287, 289, 297, 305, 307, 309, 310, 311, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 346, 373, 374, 375, 376, 377, 380, and 381.

### Claim 43 (depends on 1)

The multivalent binding protein of claim 1, wherein the C-terminus linker does not comprise (Gly4Ser)3.

### Claim 44 (depends on 1)

The multivalent binding protein of claim 1, wherein the binding protein is a single chain molecule capable of forming a dimer by disulfide bond formation.

### Claim 45 (depends on 1)

The multivalent binding protein of claim 1, wherein the constant sub-region is capable of an effector function selected from the group consisting of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, relatively extended in vivo half-life (relative to the same molecule lacking a constant sub-region), FcR binding, and protein A binding.

### Claim 46 (depends on 1)

A nucleic acid encoding the protein of claim 1.

### Claim 47 (depends on 46)

A vector comprising the nucleic acid of claim 46.

### Claim 48 (depends on 46, 47)

A host cell comprising the nucleic acid of claim 46 or the vector of claim 47.

### Claim 49 (depends on 1)

A composition comprising the protein of claim 1 and a pharmaceutically acceptable carrier.