Single chain multivalent binding proteins with effector function

• US 8,409,577 B2
• Filed: 06/12/2007
• Issued: 04/02/2013
• Est. Priority Date: 06/12/2006
• Status: Active Grant

• Current Assignee: Aptevo Reseach And Development LLC
• Original Assignee: Emergent Product Development Seattle, LLC
• Inventors: Thompson, Peter Armstrong, Ledbetter, Jeffrey A., Hayden-Ledbetter, Martha Susan, Grosmaire, Laura Sue, Bader, Robert, Brady, William
• Primary Examiner(s): HUYNH, PHUONG N
• Application Number:
  US12/304,562
• Publication Number:
  US 20110033483A1
• Time in Patent Office: 2,121 Days
• Field of Search: None
• US Class Current: 424/134.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 16/28 against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/2803 : against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2809 : against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2818 : against CD28 or CD152
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2833 : against MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 16/2851 : against the lectin superfamily, e.g. CD23, CD72
• CPC Class Codes: C07K 16/2875 : against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 against NGF C07K16/22, against TNF C07K16/241
• CPC Class Codes: C07K 16/2878 : against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/46 : Hybrid immunoglobulins hybrids of an immunoglobulin with a peptide not being an immunoglobulin C07K19/00
• CPC Class Codes: C07K 16/468 : Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/53 : Hinge
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/64 : comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

Multivalent binding peptides, including bi-specific binding peptides, having immunoglobulin effector function are provided, along with encoding nucleic acids, vectors and host cells as well as methods for making such peptides and methods for using such peptides to treat or prevent a variety of diseases, disorders or conditions, as well as to ameliorate at least one symptom associated with such a disease, disorder or condition.

Claims

1. A single-chain multispecific binding protein comprising from amino-terminus to carboxy-terminus:

(a) a first binding domain comprising variable regions from an immunoglobulin;

(b) a first linker peptide;

(c) a constant sub-region comprising an immunoglobulin C_H2 domain and a C_H3 domain;

(d) a second linker peptide, wherein said second linker peptide comprises the sequence of SEQ ID NO;

165; and

(e) a second binding domain comprising variable regions from an immunoglobulin.

2. The protein according to claim 1 wherein the first and second binding domains specifically bind different target molecules located on the same cell.

3. The protein according to claim 1 wherein the first and second binding domains specifically bind different target molecules located on physically distinct cells.

4. The protein according to claim 1 wherein at least one binding domain specifically binds a cell-free molecular target.

5. The protein according to claim 1 wherein at least one binding domain is an ssFv comprising a sequence selected from SEQ ID NO:

2, 4, 6, 103, 105, 107, and 109.

6. The protein according to claim 1 wherein the first and second binding domains comprise chimeric, humanized, or human immunoglobulin variable domains.

7. The protein according to claim 1 wherein the constant sub-region comprises IgG1 immunoglobulin C_H2 and C_H3 domains.

8. The protein according to claim 1 wherein the constant sub-region is a human immunoglobulin constant sub-region.

9. The protein according to claim 1 wherein at least one binding domain specifically binds 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.

10. The protein according to claim 1 wherein one of the two binding domains specifically binds a target selected from the group consisting of CD3, CD20, CD37, CD79b, CD80, CD86, IRTA1, IRTA2, IRTA3, IRTA4, IRTA5, TNFRI/TNFRSF1A, TNFRII/TNFRSF1B, Fas/TNFRSF6, TRAILR/TNFRSF10, RANK/TNFRSF11A, Osteoprotegerin/TNFRSF11B, TWEAKR/TNFRSF12, HVEM/TNFRSF14, GITR/TNFRSF18, TNF-α

/TNFSF1A, TNF-β

/TNFSF1B, TRAIL/TNFSF10, Fas Ligand/TNFSF6, TWEAK/TNFSF12, APRIL/TNFSF13, LIGHT/TNFSF14, GITRL/TNFSF18, FGFR, Flt-3, HGFR, IGF-IR, IGF-IIR, MSPR/Ron, PDGFRα

, PDGFRβ

, EGFR, ErbB2, ErbB3, VEGFR1/Flt-1, VEGFR2/Flt-1, VEGFR3/Flt-4, TGF-β

RI/ALK-5, TGF-β

RII, TGF, β

RIIb, TGF-α

, IGF-I, IGF-II, BMP, TGF-β

, FGF, PIGF, PDGF-A, PDGF-B, PDGF-C, PDGF-D, VEGF, VEGF-B, VEGF-C, VEGF-D, IL-2R , IL-2Rβ

, IL-4R, B7-H3, IL-6R, IL-10Rα

, IL-10β

, IL-12Rβ

, IL-12Rβ

2, IL-13Rα

I, Osteopontin, PD-1, CTLA-4, IFN-γ

R1, IFN-γ

R2, Receptor for Advanced Glycation End products (RAGE), IL-13, IL-22R, IL-21, and IL-4.

11. The protein according to claim 1 wherein the protein comprises a binding domain pair specifically recognizing a pair of antigens selected from the group consisting of CD19/CD20, CD19/CD22, CD19/CL II, CD20/CD21, CD20/CD22, CD20/CD40, CD20/CD79a, CD20/CD79b, CD20/CD81, CD20/CL II, CD21/CD22, CD21/CD79b, CD21/CL II, CD22/CD23, CD22/CD30, CD22/CD37, CD22/CD40, CD22/CD70, CD22/CD72, CD22/CD79a, CD22/CD79b, CD22/CD80, CD22/CD86, CD22/CL II, CD23/CL II, CD30/CL II, CD37/CD79b, CD37/CL II, CD40/CD79b, CD40/CL II, CD70/CD79b, CD70/CL II, CD72/CD79b, CD72/CL II, CD79a/CD79b, CD79b/CD80, CD79b/CD81, CD79b/CD86, CD79b/CL II, CD80/CL II, and CD86/CL II.

12. A composition comprising the protein according to claim 1 and a pharmaceutically acceptable adjuvant, carrier or excipient.

13. The protein according to claim 10, wherein one of the two binding domains specifically binds to IL-13.

14. The protein according to claim 10, wherein one of the two binding domains specifically binds to IL-4.

15. The protein according to claim 1, wherein the first linker peptide is at least five amino acids in length.

16. The composition of claim 12, wherein the composition comprises a plurality of said protein.

17. A protein dimer comprising two single-chain multispecific binding proteins according to claim 1.