US 11,236,150 B2Granted

Hetero-dimeric multi-specific antibody format

AssigneeNumab Therapeutics AG

InventorsSebastian Meyer, David Urech

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Abstract

The invention relates to a novel hetero-dimeric multi-specific format of multiple antibody variable domains comprising a core of two split variable domain pairs wherein both variable light domains and the two cognate variable heavy domains are positioned in tandem on two separate protein chains, respectively.

Claims17

Dependent claims

A hetero-dimeric protein comprising a first and a second single-chain protein,

wherein said first single-chain protein comprises a first amino acid sequence consisting of (from the N- to the C-terminus):
(ia) a first VL domain;
(iia) a first polypeptide linker and
(iiia) a second VL domain, and
wherein said second single-chain protein comprises a second amino acid sequence consisting of (from the N- to the C-terminus):
(ib) a first VH domain;
(iib) a second polypeptide linker and
(iiib) a second VH domain, and
wherein said first VL domain forms a first cognate pair of variable domains with specificity to a first target antigen with either said first or said second VH domain, and said second VL domain forms a second cognate pair of variable domains with specificity to a second target antigen with the other of said VH domains, and wherein at least one of said first or said second single-chain protein further comprises:
(iv) a third functional domain that is fused via a third polypeptide linker to said first or said second amino acid sequence;
(v) at least one additional domain as a fourth functional domain that is fused via a fourth polypeptide linker to said first or said second amino acid sequence, so that said hetero-dimeric protein is at least tetraspecific;
and
wherein said hetero-dimeric protein does not comprise (i) a cognate pair of a first and a second immunoglobulin constant domain, wherein said first immunoglobulin constant domain is comprised in said first single-chain protein and wherein said second immunoglobulin constant domain is comprised in said second single-chain protein, and wherein said hetero-dimeric protein does not comprise (ii) any further pair of heteroassociation domains, in which one heteroassociation domain of said further pair of heteroassociation domains is located on the first single-chain protein, and the other heteroassociation domain is located on the second single-chain protein, other than said first and second cognate pairs of variable domains,
wherein at least one of said VL and/or VH domains comprises human framework regions, wherein at least one of said VL domains comprises (i) human Vκ framework regions I to III;
(ii) CDR domains CDR1, CDR2 and CDR3;
and (iii) a framework region IV, which is a human Vλ germ line sequence for framework region IV.

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Dependencies are inferred from the claim text.

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Abstract

A hetero-dimeric protein comprising a first and a second single-chain protein,

wherein said first single-chain protein comprises a first amino acid sequence consisting of (from the N- to the C-terminus):
(ia) a first VL domain;
(iia) a first polypeptide linker and
(iiia) a second VL domain, and
wherein said second single-chain protein comprises a second amino acid sequence consisting of (from the N- to the C-terminus):
(ib) a first VH domain;
(iib) a second polypeptide linker and
(iiib) a second VH domain, and
wherein said first VL domain forms a first cognate pair of variable domains with specificity to a first target antigen with either said first or said second VH domain, and said second VL domain forms a second cognate pair of variable domains with specificity to a second target antigen with the other of said VH domains, and wherein at least one of said first or said second single-chain protein further comprises:
(iv) a third functional domain that is fused via a third polypeptide linker to said first or said second amino acid sequence;
(v) at least one additional domain as a fourth functional domain that is fused via a fourth polypeptide linker to said first or said second amino acid sequence, so that said hetero-dimeric protein is at least tetraspecific;
and
wherein said hetero-dimeric protein does not comprise (i) a cognate pair of a first and a second immunoglobulin constant domain, wherein said first immunoglobulin constant domain is comprised in said first single-chain protein and wherein said second immunoglobulin constant domain is comprised in said second single-chain protein, and wherein said hetero-dimeric protein does not comprise (ii) any further pair of heteroassociation domains, in which one heteroassociation domain of said further pair of heteroassociation domains is located on the first single-chain protein, and the other heteroassociation domain is located on the second single-chain protein, other than said first and second cognate pairs of variable domains,
wherein at least one of said VL and/or VH domains comprises human framework regions, wherein at least one of said VL domains comprises (i) human Vκ framework regions I to III;
(ii) CDR domains CDR1, CDR2 and CDR3;
and (iii) a framework region IV, which is a human Vλ germ line sequence for framework region IV.

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