Multispecific antigens binding fragments and multispecific antibodies

Patent metadata

Field	Value
Publication number	US-11945879-B2
Application number	US-202016996510-A
Country	US
Kind code	B2
Filing date	Aug 18, 2020
Priority date	Jul 7, 2011
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

The invention relates to multispecific antibody constructs comprising Fab fragments having mutations at the interface of the CH1 and CL domains, said mutations preventing heavy chain/light chain mispairing.

First claim

The invention claimed is:

1. A multispecific antibody construct comprising at least two Fab fragments with different CH1 and CL domains, wherein each Fab fragment recognizes a different epitope of interest, and wherein at least one Fab fragment is a mutated Fab fragment that comprises:
the VH and VL domains of an antibody recognizing an epitope of interest;
a CH1 domain which is derived from the CH1 domain of a human immunoglobulin by substitution of the leucine residue at position 143 of said CH1 domain with a glutamine residue and substitution of the serine residue at position 188 of said CH1 domain with a valine residue; and
a CL domain of the kappa type which is derived from the CL-kappa domain of a human immunoglobulin by substitution of the valine residue at position 133 of said CL-kappa domain with a threonine residue and substitution of the serine residue at position 176 of said CL-kappa domain with a valine residue; wherein the position numbers used for the CH1 and CL-kappa domains refer to Kabat numbering.

2. The multispecific antibody construct of claim 1 , comprising
a) at least one mutated Fab fragment consisting of:
i) the VH and VL domains of an antibody recognizing an epitope of interest;
ii) a CH1 domain of a human immunoglobulin comprising substitution of the leucine residue at position 143 of said CH1 domain with a glutamine residue and substitution of the serine residue at position 188 of said CH1 domain with a valine residue; and
iii) a CL-kappa domain of a human immunoglobulin comprising substitution of the valine residue at position 133 of said CL-kappa domain with a threonine residue and substitution of the serine residue at position 176 of said CL-kappa domain with a valine residue; and

b) at least one mutated Fab fragment consisting of:
i) the VH and VL domains of an antibody recognizing an epitope of interest;
ii) a CH1 domain of a human immunoglobulin comprising substitution of the threonine residue at position 192 of said CH1 domain with a glutamic acid residue; and
iii) a CL-kappa domain of a human immunoglobulin comprising substitution of the asparagine residue at position 137 of said CL domain with a lysine residue and substitution of the serine residue at position 114 of said CL domain with an alanine residue

wherein the position numbers used for the CH1 and CL domains refer to Kabat numbering.

3. A therapeutic composition comprising a multispecific antibody construct of claim 1 and a pharmaceutically acceptable vehicle.

Assignees

• Centre Nat Rech Scient
• Azienda Ospedaliera Papa Giovanni Xxiii
• Univ Lausanne
• Jean Kadouche
• Azienda socio sanitaria territoriale Papa Giovanni XXIII
• Univ Of Lausanne

Inventors

• Kadouche Jean
• Mach Jean-Pierre
• Michielin Olivier
• Zoete Vincent
• Iwaszkiewicz Justyna
• Cerutti Martine
• Choblet Sylvie
• Golay Josee

Classifications

• C07K16/468 Primary

  Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies · CPC title

• C07K16/2833 Primary

  against MHC-molecules, e.g. HLA-molecules · CPC title

• C07K16/2896

  against molecules with a "CD"-designation, not provided for elsewhere · CPC title

• C07K2317/31

  multispecific · CPC title

• C07K2317/522

  CH1 domain · CPC title