Compositions comprising antigen-binding molecules

Patent metadata

Field	Value
Publication number	US-12054544-B2
Application number	US-201816488115-A
Country	US
Kind code	B2
Filing date	Feb 23, 2018
Priority date	Feb 24, 2017
Publication date	Aug 6, 2024
Grant date	Aug 6, 2024

Abstract

The present invention relates to pharmaceutical compositions containing a combination of a first antigen-binding molecule and a second antigen-binding molecule, wherein the first antigen-binding molecule and the second antigen-binding molecule are not linked by a covalent bond, and they are more likely to form a heterodimer than homodimers when mixed in solution. Furthermore, the present invention relates to antigen-binding molecules, therapeutic methods, and screening methods that are associated with the combination.

First claim

The invention claimed is:

1. A first antigen-binding molecule comprising a first antigen-binding region that binds to a first antigen and a first IgG Fc domain comprising a first CH3, wherein, when mixed in solution with a second antigen-binding molecule having a second antigen-binding region that binds to a second antigen and a second IgG Fc domain comprising a second CH3, the first antigen-binding molecule is promoted to form a heterodimer with the second antigen-binding molecule and suppressed to form a homodimer of the first antigen-binding molecule, wherein the first CH3 domain comprises the D356K/V397Y/K409D, D356K/V397Y/K409H, D356K/V397Y/K409T, D356K/E357N/V397Y/K409D, D356K/E357L/V397Y/K409D, V397Y/K409D or V397Y/K409D/Y349T/T394F substitutions and the second CH3 domain comprises the V397Y/K409D/K439E, V397Y/K409H/K439E, V397Y/K409T/K439E, E357N/V397Y/K409D/K439E, E357L/V397Y/K409D/K439E, V397Y/K409D or V397Y/K409D/S364H/F405A substitutions, wherein the position of the substitutions is according to the EU numbering system, and
wherein the first and second polypeptide can form heterodimers in a surface plasmon reference assay.

2. A second antigen-binding molecule comprising a second antigen-binding region that binds to a second antigen and a second IgG Fc domain comprising a second CH3, wherein, when mixed in solution with a first antigen-binding molecule having a first antigen-binding region that binds to a first antigen and a first IgG Fc domain comprising a first CH3, the second antigen-binding molecule is promoted to form a heterodimer with the first antigen-binding molecule and suppressed to form a homodimer of the second antigen-binding molecule, wherein the first CH3 domain comprises the D356K/V397Y/K409D, D356K/V397Y/K409H, D356K/V397Y/K409T, D356K/E357N/V397Y/K409D, D356K/E357L/V397Y/K409D, V397Y/K409D or V397Y/K409D/Y349T/T394F substitutions and the second CH3 domain comprises the V397Y/K409D/K439E, V397Y/K409H/K439E, V397Y/K409T/K439E, E357N/V397Y/K409D/K439E, E357L/V397Y/K409D/K439E, V397Y/K409D or V397Y/K409D/S364H/F405A substitutions, wherein the position of the substitutions is according to the EU numbering system, and
wherein the first and second polypeptide can form heterodimers in a surface plasmon reference assay.

3. A composition, comprising
a) a first polypeptide comprising (i) a first antigen binding domain that binds to a first antigen and (ii) a first IgG Fc domain comprising a first CH3 domain, and
b) a second polypeptide comprising (i) a second antigen binding domain that binds to a second antigen and (ii) a second IgG Fc domain comprising a first CH3 domain,
wherein the first polypeptide and second polypeptide are not linked by a covalent bond,
wherein the first CH3 domain comprises the D356K/V397Y/K409D, D356K/V397Y/K409H, D356K/V397Y/K409T, D356K/E357N/V397Y/K409D, D356K/E357L/V397Y/K409D, V397Y/K409D or V397Y/K409D/Y349T/T394F substitutions and the second CH3 domain comprises the V397Y/K409D/K439E, V397Y/K409H/K439E, V397Y/K409T/K439E, E357N/V397Y/K409D/K439E, E357L/V397Y/K409D/K439E, V397Y/K409D or V397Y/K409D/S364H/F405A substitutions, wherein the position of the substitutions is according to the EU numbering system, and
wherein the first and second polypeptide can form heterodimers in a surface plasmon reference assay.

4. The composition of claim 3 , wherein
1) The first CH3 domain comprises the D356K/V397Y/K409D substitutions and the second CH3 domain comprises the V397Y/K409D/K439E substitutions,
2) The first CH3 domain comprises the D356K/V397Y/K409H substitutions and the second CH3 domain comprises the V397Y/K409H/K439E substitutions,
3) The first CH3 domain comprises the D356K/V397Y/K409T substitutions and the second CH3 domain comprises the V397Y/K409T/K439E substitutions,
4) The first CH3 domain comprises the D356K/E357N/V397Y/K409D substitutions and the second CH3 domain comprises the E357N/V397Y/K409D/K439E substitutions,
5) The first CH3 domain comprises the D356K/E357L/V397Y/K409D substitutions and the second CH3 domain comprises the E357L/V397Y/K409D/K439E substitutions,
6) The first CH3 domain comprises the V397Y/K409D substitutions and the second CH3 domain comprises the V397Y/K409D substitutions, and
7) The first CH3 domain comprises the V397Y/K409D/Y349T/T394F substitutions and the second CH3 domain comprises the V397Y/K409D/S364H/F405A substitutions.

5. The composition of claim 3 , wherein the first antigen and the second antigen are different.

6. The composition of claim 3 , wherein the first antigen binding domain comprises a first variable heavy chain region and a first variable light chain region and the second antigen binding domain comprises a second variable heavy chain region and a second variable light chain region.

7. The composition of claim 3 , wherein the first and second IgG Fc domain comprises a first and second CH2 domain, respectively, wherein the first CH2 domain comprises the L234Y/L235Q/G236W/S239M/H268D/D270E/S298A substitutions, and the second CH2 domain comprises the D270E/K326D/A330M/K334E substitutions, wherein the position of the substitutions is according to the EU numbering system.

8. The composition of claim 3 , wherein the first and second IgG Fc domains comprise the C226S and C229S substitutions, wherein the position of the substitutions is according to the EU numbering system.

9. The composition of claim 3 , wherein the surface plasmon reference assay uses a sensor chip comprising immobilized first and second antigen.

10. The first antigen-binding molecule of claim 1 , wherein
1) The first CH3 domain comprises the D356K/V397Y/K409D substitutions and the second CH3 domain comprises the V397Y/K409D/K439E substitutions,
2) The first CH3 domain comprises the D356K/V397Y/K409H substitutions and the second CH3 domain comprises the V397Y/K409H/K439E substitutions,
3) The first CH3 domain comprises the D356K/V397Y/K409T substitutions and the second CH3 domain comprises the V397Y/K409T/K439E substitutions,
4) The first CH3 domain comprises the D356K/E357N/V397Y/K409D substitutions and the second CH3 domain comprises the E357N/V397Y/K409D/K439E substitutions,
5) The first CH3 domain comprises the D356K/E357L/V397Y/K409D substitutions and the second CH3 domain comprises the E357L/V397Y/K409D/K439E substitutions,
6) The first CH3 domain comprises the V397Y/K409D substitutions and the second CH3 domain comprises the V397Y/K409D substitutions, and
7) The first CH3 domain comprises the V397Y/K409D/Y349T/T394F substitutions and the second CH3 domain comprises the V397Y/K409D/S364H/F405A substitutions.

11. The first antigen-binding molecule of claim 1 , wherein the first antigen and the second antigen are different.

12. The first antigen-binding molecule of claim 1 , wherein the first antigen binding domain comprises a first variable heavy chain region and a first variable light chain region and the second antigen binding domain comprises a second variable heavy chain region and a second variable light chain region.

13. The first antigen-binding molecule of claim 1 , wherein the first and second IgG Fc domain comprises a first and second CH2 domain, respectively, wherein the first CH2 domain comprises the L234Y/L235Q/G236W/S239M/H268D/D270E/S298A substitutions, and the second CH2 domain comprises the D270E/K326D/A330M/K334E substitutions, wherein the position of the substitutions is according to the EU numbering system.

14. The first antigen-binding molecule of claim 1 , wherein the first and second IgG Fc domains comprise the C226S and C229S substitutions, wherein the position of the substitutions is according to the EU numbering system.

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Igawa Tomoyuki
• Katada Hitoshi
• Kawai Takeaki

Classifications

• G01N33/6854

  Immunoglobulins · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/526

  CH3 domain · CPC title

• A61K2039/505

  comprising antibodies · CPC title