公开(公告)号：US11059898B2

公开(公告)日：2021-07-13

申请号：US15128781

申请日：2015-03-24

Applicant: UNIVERSITY OF SOUTHAMPTON

Inventor： Martin J. Glennie ,  Ann White

IPC: C07K16/28 ,  C07K16/24 ,  C07K16/30 ,  A61K39/00

Abstract: Through a combination of in vitro and in vivo approaches, the inventors show that human IgG2 (h2) delivers unique FcγR-independent agonistic activity to anti-CD40 antibodies and to antibodies specific to other immunostimulatory receptors, including 4-1BB and CD28. Investigation of an anti-human CD40 mAb, LOB7.4, revealed that the unique activity of h2 was dependent upon the precise arrangement of hinge and CH1 disulfide bonds. Chemical ‘shuffling’ or mutagenesis to ‘lock’ LOB7.4 into either a more flexible ‘h2A’ or more compact ‘h2B’ conformation endowed antagonistic and agonistic properties, respectively. Engineering of h2 in this way allows development of reagents with either immunostimulatory or immunosuppressive characteristics, with direct implication for the design of therapeutic mAb agents and fusion proteins.

公开(公告)号：US20170158771A1

公开(公告)日：2017-06-08

申请号：US15128781

申请日：2015-03-24

Applicant: UNIVERSITY OF SOUTHAMPTON

Inventor： Martin J. Glennie ,  Ann White

IPC: C07K16/28 ,  C07K16/30

CPC classification number: C07K16/2878 ,  A61K2039/505 ,  C07K16/2818 ,  C07K16/30 ,  C07K2317/24 ,  C07K2317/522 ,  C07K2317/53 ,  C07K2317/70 ,  C07K2317/75 ,  C07K2317/76

Abstract: Through a combination of in vitro and in vivo approaches, the inventors show that human IgG2 (h2) delivers unique FcγR-independent agonistic activity to anti-CD40 antibodies and to antibodies specific to other immunostimulatory receptors, including 4-1BB and CD28. Investigation of an anti-human CD40 mAb, LOB7.4, revealed that the unique activity of h2 was dependent upon the precise arrangement of hinge and CH1 disulfide bonds. Chemical ‘shuffling’ or mutagenesis to ‘lock’ LOB7.4 into either a more flexible ‘h2A’ or more compact ‘h2B’ conformation endowed antagonistic and agonistic properties, respectively. Engineering of h2 in this way allows development of reagents with either immunostimulatory or immunosuppressive characteristics, with direct implication for the design of therapeutic mAb agents and fusion proteins.