Bispecific 2+1 contorsbodies

Patent metadata

Field	Value
Publication number	US-12227594-B2
Application number	US-201816760820-A
Country	US
Kind code	B2
Filing date	Oct 31, 2018
Priority date	Nov 1, 2017
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

Abstract

The invention relates to novel bispecific antibodies consisting of two fusion polypeptides comprising two antigen binding domains capable of specific binding to a first target and one antigen binding domain capable of specific binding to a second target, and to methods of producing these molecules and to methods of using the same.

First claim

The invention claimed is:

1. A bispecific antibody comprising two fusion polypeptides and comprising 2+1 binding domains binding domain capable of specific binding to a tumor-specific antigen comprising:
(a)
(1) a first fusion polypeptide from N-terminus to C-terminus comprising a first heavy chain variable domain (first VH), a CH1 domain, a first peptide linker, a spacer domain, a second peptide linker, a first light chain variable domain (first VL), a CL domain (Ckappa), a third peptide linker, a second light chain variable domain (second VL), and a CH1 domain, wherein the first VH and the first VL forms a first binding domain, and
(2) a second fusion polypeptide from N terminus to C-terminus comprising a first heavy chain variable domain (first VH), a CH1 domain, a first peptide linker, a spacer domain, a second peptide linker, a first light chain variable domain (first VL), a CL domain (Ckappa), a third peptide linker, a second heavy chain variable domain (second VH), and a CL domain (Ckappa),
wherein the first VH and the first VL forms a first binding domain, and wherein the second VH and the second VL domain forms a second antigen binding domain, wherein the spacer domain comprises a hinge, a CH2 domain and a CH3 domain or a fragment thereof;

or
(b)
(1) a first fusion polypeptide from N-terminus to C-terminus comprising a first heavy chain variable domain (first VH), a CL domain (Ckappa), a first peptide linker, a spacer domain, a second peptide linker, a first light chain variable domain (first VL), a CH1 domain, a third peptide linker, a second heavy chain variable domain (second VH), and a CH1 domain, wherein the first VH and the first VL forms a first binding domain, and
(2) a second fusion polypeptide from N-terminus to C-terminus comprising a first heavy chain variable domain (first VH), a CL domain (Ckappa), a first peptide linker, a spacer domain, a second peptide linker, a first light chain variable domain (first VL), a CH1 domain, a third peptide linker, a second light chain variable domain (second VL), and a CL domain (Ckappa),
wherein the first VH and the first VL forms a first binding domain, and wherein the second VH and the second VL domain forms a second antigen binding domain, wherein the spacer domain comprises a hinge, a CH2 domain and a CH3 domain or a fragment thereof,

or
(c)
(1) a first fusion polypeptide from N-terminus to C-terminus comprising a first light chain variable domain (first VL), a CL domain (Ckappa), a first peptide linker, a spacer domain, a second peptide linker, a first heavy chain variable domain (first VH), a CH1 domain, a third peptide linker, a second light chain variable domain (second VL), and a CH1 domain, wherein the first VH and the first VL forms a first binding domain, and
(2) a second fusion polypeptide from N-terminus to C-terminus comprising a first light chain variable domain (first VL), a CL domain (Ckappa), a first peptide linker, a spacer domain, a second peptide linker, a first heavy chain variable domain (first VH), a CH1 domain, a third peptide linker, a second heavy chain variable domain (second VH), and a CL domain (Ckappa),
wherein the first VH and the first VL forms a first binding domain, and wherein the second VH and the second VL domain forms a second antigen binding domain, wherein the spacer domain comprises a hinge, a CH2 domain and a CH3 domain or a fragment thereof,

or
(d)
(1) a first fusion polypeptide from N-terminus to C-terminus comprising a second light chain variable domain (second VL), a CH1 domain, a first peptide linker, a first heavy chain variable domain (first VH), a CL domain (Ckappa) a second peptide linker, a spacer domain, a third peptide linker, a first light chain variable domain (first VL) and a CH1 domain, wherein the first VH and the first VL forms a first binding domain, and
(2) a second fusion polypeptide from N-terminus to C-terminus comprising a second heavy chain variable domain (second VH), a CL domain (Ckappa), a first peptide linker, a first heavy chain variable domain (first VH), a CL domain (Ckappa), a second peptide linker, a spacer domain, a third peptide linker, a first light chain variable domain (first VL) and a CH1 domain,
wherein the first VH and the first VL forms a first binding domain, and wherein the second VH and the second VL domain forms a second antigen binding domain, wherein the spacer domain comprises a hinge, a CH2 domain and a CH3 domain or a fragment thereof;

wherein for each of (a)-(d) above, the first and second antigen binding domain are associated with each other to form a circular fusion polypeptide, and wherein the spacer domain of the first fusion polypeptide and the spacer domain of the second fusion polypeptide are associated covalently to each other by a disulfide bond and comprise at least one modification promoting the association of the first fusion polypeptide and second fusion polypeptide.

2. The bispecific antibody of claim 1 , wherein:
(a) each of said first VH comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:17, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 19, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:22, and each of said first VL comprises (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:31, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:35, or
(b) each of said first VH comprises (1) CDR-H1 comprising the amino acid sequence of SEQ ID NO:17, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:19, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:21, and each of said first VL comprises (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:31, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:34, or
(c) each of said first VH comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:17, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:19, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:23, and each of said first VL comprises (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:31, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:36, or
(d) each of said first VH comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:17, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:19, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:24, and each of said first VL comprises (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:28, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:31, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:37, or
(e) each of said first VH comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:18, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:25, and each of said first VL comprises (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:29, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:32, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:38, or
(f) each of said first VH comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:18, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:20, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:26, and each of said first VL comprises (iv) CDR-L1 comprising the amino acid sequence of SEQ ID NO:29, (v) CDR-L2 comprising the amino acid sequence of SEQ ID NO:32, and (vi) CDR-L3 comprising the amino acid sequence of SEQ ID NO:38, or
(g) each of said first VH comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:18, (ii) CDR-H2 comprising the amino acid

Assignees

• Hoffmann La Roche

Inventors

• Amann Maria
• Ferrara Koller Claudia
• Flury Reto
• Georges Guy
• Grau-Richards Sandra
• Haas Alexander
• Hesse Friederike
• Imhof-Jung Sabine
• Klein Christian

Classifications

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/55

  Fab or Fab' · CPC title

• C07K2317/53

  Hinge · CPC title

• C07K2317/526

  CH3 domain · CPC title