Monovalent Antigen Binding Proteins

• US 20120237507A1
• Filed: 02/27/2012
• Published: 09/20/2012
• Est. Priority Date: 02/28/2011
• Status: Abandoned Application

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Bossenmaier, Birgit, Kettenberger, Hubert, Klein, Christian, Kuenkele, Klaus-Peter, Regula, Joerg-Thomas, Schaefer, Wolfgang, Schwaiger, Manfred, Sustmann, Claudio
• Application Number:
  US13/406,503
• Publication Number:
  US 20120237507A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• 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 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/35 Valency
• CPC Class Codes: C07K 2317/64 comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/66 comprising a swap of domains, e.g. CH3-CH2, VH-CL or VL-CH1
• CPC Class Codes: C07K 2317/732 Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present invention relates to monovalent antigen binding proteins with a CH1-CL domain exchange, methods for their production, pharmaceutical compositions containing said antibodies, and uses thereof.

Claims

1. A monovalent antigen binding protein comprising

a) a modified heavy chain of an antibody which specifically binds to an antigen, wherein the VH domain is replaced by the VL domain of said antibody;

and

b) a modified heavy chain of said antibody, wherein the CH1 domain is replaced by the CL domain of said antibody.

2. The monovalent antigen binding protein according to claim 1, comprising

the CH3 domain of the modified heavy chain of the antibody of a) and the CH3 domain of the modified heavy chain of the antibody of b) each meet at an interface which comprises an original interface between the antibody CH3 domains;

wherein said interface is altered to promote the formation of the monovalent antigen binding protein, wherein the alteration comprises;

i) a CH3 domain of one heavy chain is altered,

so that within the original interface the CH3 domain of one heavy chain that meets the original interface of the CH3 domain of the other heavy chain within the monovalent antigen binding protein,

an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the interface of the CH3 domain of one heavy chain which is positionable in a cavity within the interface of the CH3 domain of the other heavy chain

and

ii) the CH3 domain of the other heavy chain is altered,

so that within the original interface of the second CH3 domain that meets the original interface of the first CH3 domain within the monovalent antigen binding protein,

an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the interface of the second CH3 domain within which a protuberance within the interface of the first CH3 domain is positionable.

3. The monovalent antigen binding protein according to claim 2, comprising said amino acid residue having a larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), tryptophan (W), and said amino acid residue having a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), valine (V).

4. The monovalent antigen binding protein according to claim 3, comprising both CH3 domains are further altered by the introduction of cysteine (C) as amino acid in the corresponding positions of each CH3 domain such that a disulfide bridge between both CH3 domains can be formed.

5. The monovalent antigen binding protein according to claims 1 to 4, comprising is of human IgG1 isotype.

6. The monovalent antigen binding protein according to claim 1, characterized in comprising

a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO:

1; and

b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

2;

or

a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

3; and

b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

4;

or

a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

5; and

b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

6;

or

a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

7; and

b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

8;

or

a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

9; and

b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

10;

or

a) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

11; and

b) a modified heavy chain comprising the amino acid sequence of SEQ ID NO;

12.

7. The monovalent antigen binding protein according to claim 1, 2, 3, 4 or 6, comprising the modified heavy chains of a) and b) are of IgG1 isotype, and the antigen binding protein is afucosylated with an amount of fucose of 80% or less of the total amount of oligosaccharides (sugars) at Asn297 is of human IgG1 isotype.

8. A pharmaceutical composition of a monovalent antigen binding protein according to claims 1 to 7.

9. A pharmaceutical composition comprising a monovalent antigen binding protein according to claims 1 to 7 and at least one pharmaceutically acceptable excipient.

10. The monovalent antigen binding protein according to claims 1 to 7 for use in the treatment of cancer.

11. Use of the monovalent antigen binding protein according to claims 1 to 7 for the manufacture of a medicament for the treatment of cancer.

12. A method for the treatment of a patient in need of therapy, characterized by administering to the patient a therapeutically effective amount of a monovalent antigen binding protein according to claims 1 to 7.

13. A method for the preparation of a monovalent antigen binding protein according to claims 1 to 7

comprising the steps of

a) transforming a host cell with vectors comprising nucleic acid molecules encoding a monovalent antigen binding protein according to claims 1 to 7,

b) culturing the host cell under conditions that allow synthesis of said monovalent antigen binding protein molecule;

and

c) recovering said monovalent antigen binding protein molecule from said culture.

14. Nucleic acid encoding the monovalent antigen binding protein according to claims 1 to 7.

15. A vector comprising nucleic acid according to claim 14.

16. A host cell comprising the vector according to claim 15.