Methods of treating her2-positive cancers using pd-1 axis binding antagonists and Anti-her2 antibodies

Abstract

The invention provides compositions and methods for treating HER2-postitive cancers. The method comprising administering a PD-1 axis binding antagonist and an antibody that targets HER2.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the priority benefit of U.S. Provisional Application No. 61 / 917,264, filed Dec. 17, 2013, which is hereby incorporated by reference in its entirety.SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE[0002]The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 146392022840 SeqList.txt, date recorded: Dec. 16, 2014, size: 37 KB).FIELD OF THE INVENTION[0003]This invention relates to methods of treating HER2-positive cancers by administering a PD-1 axis binding antagonist and an anti-HER2 antibody.BACKGROUND OF THE INVENTION[0004]The provision of two distinct signals to T-cells is a widely accepted model for lymphocyte activation of resting T lymphocytes by antigen-presenting cells (APCs). Lafferty et al, Aust. J. Exp. Biol. Med. Sci 53: 27-42 (1975). This model further provides for the discriminati...

AI Technical Summary

Benefits of technology

[0025]In some embodiments, the antibody described herein (e.g., a PD-1 axis binding antagonist antibody, an anti-HER2 antibody, or a bispecific antibody that binds to HER2 and a CD3) comprises an aglycosylation site mutation. In some embodiments, the aglycosylation site mutation is a substitution mutation. In some embodiments, the substitution mutation is at amino acid residue N297, L234, L235, and / or D265 (EU numbering). In some embodiments, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A. In some embodiments, the substitution mutation is a D265A mutation and an N297G mutation. In some embodiments, the aglycosylation site mutation reduces effector function of the antibody. In some embodiments, the PD-1 axis binding antagonist (e.g., an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-PD-L2 antibody) is a human IgG1 having Asn to Ala substitution at position 297 according to EU numbering.

[0029]In some embodiments of the methods, uses, compositions and kits described above and herein, CD8 T cells in the individual have enhanced priming, activation, proliferation and / or cytolytic activity relative to prior to the administration of the combination. In some embodiments, the number of CD8 T cells is elevated relative to prior to administration of the combination. In some embodiments, the CD8 T cell is an antigen-specific CD8 T cell. In some embodiments, Treg function is suppressed relative to prior to the administration of the combination. In some embodiments, T cell exhaustion is decreased relative to prior to the administration of the combination.

Problems solved by technology

In the absence of co-stimulation, T-cells can become refractory to antigen stimulation, do not mount an effective immune response, and further may result in exhaustion or tolerance to foreign antigens.

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