Compositions and methods for simultaneous bivalent and monovalent co-engagement of antigens

Patent metadata

Field	Value
Publication number	US-9493578-B2
Application number	US-87501510-A
Country	US
Kind code	B2
Filing date	Sep 2, 2010
Priority date	Sep 2, 2009
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Immunoglobulin compositions that simultaneously co-engage antigens, where one of the antigens is bound bivalently and the other antigen is bound monovalently. The novel immunoglobulins described preferably utilize heterodimeric Fc regions.

First claim

We claim:

1. An antibody analog comprising:
a) a first heavy chain and an associated light chain, wherein said first heavy and light chains form a first antigen binding site, wherein the C-terminus of the CH3 domain of said first heavy chain is covalently attached to a C-terminal variable heavy domain, wherein said first heavy chain comprises a first variant Fc domain;
b) a second heavy chain and an associated light chain, wherein said second heavy and light chains form a second antigen binding site, wherein the C-terminus of the CH3 domain of said second heavy chain is covalently attached to a C-terminal variable light domain; wherein said second heavy chain comprises a second variant Fc domain;
such that said C-terminal variable heavy and light domains form a third antigen binding site, wherein said first and second variant Fc domains are different, and wherein the first and second variant Fc domains have amino acid substitutions selected from the following pairs:

A
B

K409E and
L368K;

S364D/K370G and
S364Y/K370R;

S364D and
Y349K;

K409D and
L368K;

K392E and
D399K;

S364E and
Y349K;

L368E/K409E and
L368K;

S364E/F405A and
Y349K/T394F;

S364H and
Y349K;

P395T/V397S/F405A and
T394F;

T394S/P395V/P396T/V397E/F405S and
T394F;

V397S/F405A and
T394F;

S364H/D401K/F405A and
Y349T/T394F/T411E;

L351K/S364H/D401K and
Y349T/L351E/T411E;

S364H and
Y349T;

S364H/D401K and
Y349T/T411E;

S364H/T394F and
Y349T/F405A;

S364H/F405A and
Y349T/T394F;

F405A and
T394F;

S364E/T394F and
Y349K/F405A;

V397T/F405S and
T394F;

S364E/F405S and
Y349K/T394Y;

S364E/T411E/F405A and
Y349K/T394F/D401K;

S364E/T411E and
Y349K/D401K;

L351E/S364D and
Y349K/L351K;

L351E/S364E and
Y349K/L351K;

Y349C/S364E and
Y349K/S354C;

S364H/F405A/T411E and
Y349T/T394F/D401K;

S364D/T394F and
Y349K/F405A

and wherein numbering is according to the EU index as in Kabat and wherein the substitution(s) of column A and column B are in different heavy chains selected from the first heavy chain and the second heavy chain.

2. The antibody analog of claim 1 , wherein the first and second variant Fc domains have amino acid substitutions selected from the following pairs:

C
D

S364E/F405A and
Y349K/T394F;

S364H/D401K and
Y349T/T411E;

S364H/T394F and
Y349T/F405A;

S364E/T394F and
Y349K/F405A;

S364E/T411E and
Y349K/D401K;

S364D/T394F and
Y349K/F405A;

S364H/F405A and
Y349T/T394F

and wherein the substitution(s) of column C and column D are in different heavy chains selected from the first heavy chain and the second heavy chain.

3. An antibody analog according to claim 1 wherein two of said antigen binding sites are the same and the third is different.

4. An antibody analog according to claim 1 wherein the antigen bound by said third antigen binding site is CD3.

5. An antibody analog according to claim 1 wherein the antigen bound by said third antigen binding site is FcγRIIb.

6. An antibody analog according to claim 1 wherein all three of said antigen binding sites are the same.

7. An antibody analog according to claim 1 wherein said the C-terminus of said C-terminal variable heavy domain is covalently attached to a CH1 domain and wherein said C-terminus of said C-terminal variable light domain is covalently attached to a CL domain.

8. An antibody analog according t

Assignees

• Lazar Gregory A
• Moore Gregory L
• Xencor Inc

Inventors

• Lazar Gregory A
• Moore Gregory L

Classifications

• C07K16/468 Primary

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

• C07K2317/31

  multispecific · CPC title

• C07K2317/64

  comprising a combination of variable region and constant region components · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• C07K2317/52

  Constant or Fc region; Isotype · CPC title