Multivalent antibodies and uses therefor

• US 8,722,859 B2
• Filed: 05/11/2012
• Issued: 05/13/2014
• Est. Priority Date: 04/11/2000
• Status: Expired due to Fees

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Miller, Kathy L., Presta, Leonard G.
• Primary Examiner(s): BRISTOL, LYNN ANNE
• Application Number:
  US13/470,189
• Publication Number:
  US 20120238728A1
• Time in Patent Office: 732 Days
• Field of Search: 530/387.3
• US Class Current: 530/387.3
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6879 the immunoglobulin having two or more different antigen-binding sites, e.g. bispecific or multispecific immunoglobulin
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 16/468 Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/64 comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

The present application describes engineered antibodies, with three or more functional antigen binding sites, and uses, such as therapeutic applications, for such engineered antibodies.

Claims

1. An isolated antibody comprising two heavy chain polypeptides, four light chain polypeptides and four antigen binding sites,

wherein each of the two heavy chain polypeptides comprises

VD1-(X1)n-VD2-(X2)n-Fc,

wherein VD1 is a first VH domain, VD2 is a second VH domain, Fc is an Fc region, X1 and X2 each represents an optional intervening amino acid or polypeptide, and n is 0 or 1;

and

each of the four light chain polypeptides comprises a VL domain that forms one of the four antigen binding sites with one of the VH domains from one of the two heavy chain polypeptides.

2. The isolated antibody of claim 1, wherein the antibody binds to an antigen selected from the group consisting of HER2, DR5 and CD20.

3. The isolated antibody of claim 1, wherein VD1-(X1)n-VD2-(X2)n-Fc of each of the two heavy chain polypeptides comprises VH-CH1-VH-CH1-Fc wherein CH1 is a heavy chain constant domain and each of the four light chain polypeptides further comprises a light chain constant (CL) domain.

4. The isolated antibody of claim 1, wherein VD1-(X1)n-D2-(X2)n-Fc of each of the two heavy chain polypeptides comprises

VH-CH1-flexible linker-VH-CH1-Fc, wherein CH1 is a heavy chain constant domain, flexible linker is the amino acid sequence of glycine-serine or glycine-serine-glycine-serine (SEQ ID NO:

10) and each of the four light chain polypeptides further comprises a CL domain.