Manipulation of the hinge region to promote antibody dimerization

JP2026098045APending Publication Date: 2026-06-16AMGEN INC
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
AMGEN INC
Filing Date
2026-03-12
Publication Date
2026-06-16

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Abstract

This provides heteromultimers containing hinge regions with a small number of manipulated mutations that can successfully promote heavy chain dimerization on their own. [Solution] A heteropolymer is provided which comprises a heterodimer immunoglobulin hinge domain comprising a first immunoglobulin hinge domain polypeptide and a second immunoglobulin hinge domain polypeptide, (i) the first immunoglobulin hinge domain polypeptide comprising the following amino acid substitutions: P243K, A244K, P245K, N / E246K and L247K, and (ii) the second immunoglobulin hinge domain polypeptide comprising the following amino acid substitutions: P243D, A244D, P245D, N / E246D and L247D, wherein the numbering of amino acid residues follows the EU index described in Kabat.
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Claims

1. A heteropolymer existing independently, wherein the heteropolymer comprises a heterodimer immunoglobulin hinge domain comprising a first immunoglobulin hinge domain polypeptide and a second immunoglobulin hinge domain polypeptide, (i) The first immunoglobulin hinge domain polypeptide comprises the following amino acid substitutions: P243K, A244K, P245K, N / E246K and L247K, and (ii) The second immunoglobulin hinge domain polypeptide comprises the following amino acid substitutions: P243D, A244D, P245D, N / E246D and L247D, The numbering of amino acid residues follows the EU index listed in Kabat. A heteromultimer that exists independently.

2. The heteropolymer according to claim 1, wherein each hinge domain polypeptide further comprises an L248C substitution.

3. A heteropolymer existing independently, wherein the heteropolymer comprises a heterodimer immunoglobulin hinge domain comprising a first immunoglobulin hinge domain polypeptide and a second immunoglobulin hinge domain polypeptide, (i) The first immunoglobulin hinge domain polypeptide comprises the following amino acid substitution: A244H, and (ii) The second immunoglobulin hinge domain polypeptide comprises the following amino acid substitutions: N / E246D and L247D, The numbering of amino acid residues follows the EU index listed in Kabat. A heteromultimer that exists independently.

4. The heteropolymer according to claim 3, wherein each hinge domain polypeptide further comprises an L248C substitution.

5. A heteropolymer existing independently, wherein the heteropolymer comprises a heterodimer immunoglobulin hinge domain comprising a first immunoglobulin hinge domain polypeptide and a second immunoglobulin hinge domain polypeptide, (i) The first immunoglobulin hinge domain polypeptide comprises the following amino acid substitutions: H237K, T238K, A244K and N / E246K, and (ii) The second immunoglobulin hinge domain polypeptide comprises the following amino acid substitutions: H237D, T238D, A244D and N / E246D, The numbering of amino acid residues follows the EU index listed in Kabat. A heteromultimer that exists independently.

6. The heteropolymer according to claim 5, wherein each hinge domain polypeptide further comprises an L248C substitution.

7. A heteropolymer existing alone according to any one of claims 1 to 6, wherein each immunoglobulin hinge domain polypeptide further comprises a CH3 domain.

8. A heteropolymer existing alone according to claim 7, wherein one CH3 domain contains the mutation F405L, F405A, F405D, F405E, F405H, F405I, F405K, F405M, F405N, F405Q, F405S, F405T, F405V, F405W, or F405Y, and the other CH3 domain contains the mutation K409R, and the numbering of amino acid residues follows the EU index listed in Kabat.

9. A heteromultimer existing alone according to claim 7, wherein one CH3 domain contains the T366W mutation, and the other CH3 domain contains the T366S, L368A, and Y407V mutations, and the amino acid residue numbering follows the EU index listed in Kabat.

10. A heteromultimer existing alone according to claim 7, wherein one CH3 domain contains the K / R409D and K392D mutations, and the other CH3 domain contains the D399K and E356K mutations, and the amino acid residue numbering follows the EU index listed in Kabat.

11. A heteromultimer existing alone according to any one of claims 8 to 10, wherein one CH3 domain contains the Y349C mutation, and the other CH3 domain contains either the E356C or S354C mutation, and the amino acid residue numbering follows the EU index listed in Kabat.

12. A heteromultimer existing alone according to claim 7, wherein one CH3 domain contains the Y349C and T366W mutations, and the other CH3 domain contains the E356C, T366S, L368A and Y407V mutations, and the amino acid residue numbering follows the EU index listed in Kabat.

13. A heteromultimer existing alone according to claim 7, wherein one CH3 domain contains the Y349C and T366W mutations, and the other CH3 domain contains the S354C, T366S, L368A, and Y407V mutations, and the amino acid residue numbering follows the EU index listed in Kabat.

14. The heteromultimer that exists independently according to any one of claims 1 to 13, wherein the immunoglobulin hinge region is an IgG1 hinge region.

15. A heteromultimer existing alone according to any one of claims 1 to 14, which is a bispecific or multispecific antibody.