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US 12,180,279 B2Granted
Method for in vivo generation of multispecific antibodies from monospecific antibodies
AssigneeHoffmann-La Roche Inc.
InventorsUlrich Brinkmann, Klaus Mayer, Steffen Dickopf
Life of this patent
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Abstract
Herein is reported a method for the generation of multispecific antibodies directly on the cell-surface at the site of action by a half-antibody exchange reaction between two 2/3-IgGs or two 2/3-BiFabs destabilized in one half by asymmetric perturbing mutations fostering the generation of correctly assembled full length bi- or multispecific antibodies. The method is performed in the absence hinge region disulfide bonds in the starting 2/3-IgGs or 2/3-BiFabs.
Claims18
A multimeric polypeptide comprising
- a first polypeptide comprising
- i) in N- to C-terminal direction a) a first antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a first target, and b) a first human immunoglobulin G CH3 domain, and
- ii) a pair of an antibody light and heavy chain variable domain specifically binding to a second target either N-terminal to the first antibody variable domain or C-terminal to the first CH3 domain, and
- a second polypeptide comprising
- in N- to C-terminal direction a) a second antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a third target, and b) a second human immunoglobulin G CH3 domain, wherein the second polypeptide lacks a pair of an antibody light and heavy chain variable domain specifically binding to a target,
- wherein the second antibody variable domain is an antibody light chain variable domain if the first antibody variable domain is an antibody heavy chain variable domain;
- or the second antibody variable domain is an antibody heavy chain variable domain if the first antibody variable domain is an antibody light chain variable domain,
- and
- wherein the second CH3 domain comprises a perturbing mutation selected from the group of mutations consisting of D356K, E357K, K370E and K439E, wherein the first CH3 domain comprises
- a) the amino acid residue K at position 439 if the perturbing mutation is D356K, or
- b) the amino acid residue K at position 370 if the perturbing mutation is E357K, or
- c) the amino acid residue E at position 357 if the perturbing mutation is K370E, or
- d) the amino acid residue D at position 356 if the perturbing mutation is K439E,
- wherein all numbering is according to Kabat EU index.
11 more elements
A multimeric polypeptide comprising
- a first polypeptide comprising
- i) in N- to C-terminal direction a) a first human immunoglobulin G CH3 domain, and b) a first antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a first target,
- ii) a pair of an antibody light and heavy chain variable domain specifically binding to a second target either N-terminal to the first CH3 domain or C-terminal to the first variable domain,
- a second polypeptide comprising
- in N- to C-terminal direction a) a second human immunoglobulin G CH3 domain and b) a second antibody variable domain selected from a pair of an antibody light and heavy chain variable domain specifically binding to a third target,
- wherein the second antibody variable domain is an antibody light chain variable domain if the first antibody variable domain is an antibody heavy chain variable domain;
- or the second antibody variable domain is an antibody heavy chain variable domain if the first antibody variable domain is an antibody light chain variable domain,
- and
- wherein the second CH3 domain comprises a perturbing mutation selected from the group of mutations consisting of D356K, E357K, K370E and K439E, whereby the first CH3 domain comprises
- a) the amino acid residue K at position 439 if the perturbing mutations is D356K, or
- b) the amino acid residue K at position 370 if the perturbing mutations is E357K, or
- c) the amino acid residue E at position 357 if the perturbing mutations is K370E, or
- d) the amino acid residue D at position 356 if the perturbing mutations is K439E,
- wherein all numbering is according to Kabat EU index.
11 more elements
Dependencies are inferred from the claim text.