Anti-death receptor antibodies and methods of use thereof

Abstract

The present invention relates to monospecific or bispecific antibody molecules that specifically bind antigens of Death Receptors, which are members of the tumor necrosis factor (TNF) receptor Superfamily (TNFR-SF) with an intracellular death domain. The invention relates in particular to antibody molecules of the IgG1 isotype having a mutation in the Fc region that enhances clustering of IgG molecules after target binding. The invention further relates to a combination of antibody molecules binding different epitopes on one or more specific Death Receptors. The invention also relates to pharmaceutical compositions containing these molecules and the treatment of cancer using these compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a 35 U.S.C. 371 national stage filing of International Application No. PCT / EP2016 / 079517, filed Dec. 1, 2016, which claims priority to Danish Patent Application Nos. PA 2015 00771, filed Dec. 1, 2015, PA 2015 00787, filed Dec. 7, 2015, PA 2015 00788, filed Dec. 7, 2015, PA 2016 00701, filed Nov. 10, 2016, and PA 2016 00702, filed Nov. 10, 2016. The contents of the aforementioned applications are hereby incorporated by reference.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jan. 29, 2019, is named GMI_169BUS_Sequence_Listing.txt and is 72,344 bytes in size.FIELD OF THE INVENTION[0003]The present invention relates to monospecific or bispecific antibodies that specifically bind antigens of Death Receptors, which are members of the tumor necrosis factor (TN...

AI Technical Summary

Benefits of technology

[0006]Surprisingly the inventors of the present invention have found that the introduction of a specific point mutation in the Fc region of antibodies that specifically bind antigens of Death Receptors, which are members of the TNFR-SF comprising an intracellular death domain significantly enhances the potency of the antibody in vitro and in vivo by FcγR-independent clustering after binding of the antibody to the target on the cell surface. Even more surprisingly the inventors have also found that a combination of two anti-Death Receptor antibodies with a mutations in the Fc region facilitate antibody clustering conditional on cell surface antigen binding, resulting in the formation of hetrohexamers and enhanced potency compared to a combination of the two anti-Death Receptor antibodies without the mutation.

[0022]The antibodies and compositions of the present invention can generally be used to modulate the activity of a Death Receptor such as FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR. In one embodiment the antibody or composition may trigger, activate and / or increase or enhance the signalling that is mediated by a Death Receptor such as FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR. In one embodiment the antibody or composition may have an agonistic effect on a Death Receptor such as FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR and in particular trigger or increase the biological mechanisms, responses and effects associated with FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR, their signalling and / or the pathway in which FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR is involved. That is antibodies or compositions of the present invention may induce apoptosis or cell death in cells or tissues expressing FAS, DR4, DR5, TNFR1, DR6, DR3, EDAR or NGFR, such as cancer cells or tumor cells.

Problems solved by technology

However, these efforts only resulted in limited clinical efficacy.

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