Invented by Mark F. Maurer, Tseng-hui Timothy Chen, Brigitte Devaux, Mohan Srinivasan, Susan H. Julien, Paul O. Sheppard, Daniel F. Ardourel, Indrani Chakraborty, Bristol Myers Squibb Co
The Bristol Myers Squibb Co invention works as followsThe present invention contains antibodies, or antigen-binding fragments thereof, which bind to TIGIT (human T cell immunoreceptor, with Ig, and ITIM domains). These antibodies or fragments can be used in therapeutic applications such as the treatment of cancer, chronic viral infection, or other medical conditions. Combination therapy can be used to treat immunomodulatory receptor interactions such as the PD-1 and PD-L1 interactions. The invention also provides polynucleotides that encode the heavy or light chain variable area of antibodies, expression vectors that include the polynucleotides, cells containing the vectors, as well as methods for making antibodies or fragments from cells.
Background for Antibodies to Tigit
TIGIT (T cell immunereceptor with Ig, ITIM domains) can also be known as WUCAM or Vstm3 and Vsig9. TIGIT was found in genomic searches for proteins expressed on T cells. It has an immunoglobulin variable and transmembrane domains, an immunoreceptor-tyrosine-based inhibitory mole (ITIM), as well as signature sequence elements from the PVR protein families. It has been shown to interact with the poliovirus receptor (PVR; CD155), and with nectin2(CD112). See e.g. Stengel et al. (2012) Proc. Nat’l Acad. Sci. Sci. While PVR could interact with the coactivating receptor DNAM-1(CD226) to increase tumor killing, the high-affinity TIGIT/PVR interaction would prevent such killing and may also act to stop the killing of normal (self-expressed) cells. Stanietsky et al. (2009) Proc. Nat’l Acad. Sci. (USA) 106:17858. Although the dominance of this inhibitory interaction is important for suppression of anti-self immuno reactions, it is also crucial in tumor suppression. Id.
TIGIT inhibits T cell activation through the promotion of mature immunoregulatory cells. Yu et al. (2009) Nat. Immunol. 10:48. TIGIT and co-inhibitory compounds (e.g. TIGIT and other co-inhibitory molecules (e.g., PD-1 or Lag3) may be involved in the evasion of immune surveillance by tumor cells. Inozume and colleagues. (2014) Experiments showed that PVR/CD155 was overexpressed in melanoma cells. (2014) J. Invest. Dermatol. 134:S121.Abstract 693). and other types of tumors. The possibility exists that TIGIT/PVR interactions can protect such tumor cells against immune-mediated elimination by inducing anti-tumor reactions of T and NK. Stanietsky et al. (2009) Proc. Nat’l Acad. Sci. Sci. (2012) J. Immunol. 188:3869. Other studies have shown that a subset of regulatory T cell (Tregs), called TIGIT+, selectively suppresses Th1 and Th17 response (Joller und al. (2014) Immunity 40.569. This suggests an alternative mechanism through which anti-TIGIT antibodies may increase anti-tumor immunity response.
TIGIT might act to?turn on? The immune response is similar to that of other co-inhibitory receptors like PD-1, CTLA-4 and BTLA. Id. Id. Treatment of cancers might also be possible with antibodies that bind human TIGIT. See e.g. WO 2006/124667. Antibody blockade of PD-L1 as well as TIGIT in mouse models leads to a synergistic increase of CD8+ T cells mediated tumor rejection. Grogan et al. (2014) J. Immunol. 192(1) Suppl. 203.15; Johnston et al. (2014) Cancer Cell 26.1-15. Similar results were obtained in animal models for melanoma. Inozume et al. (2014) J. Invest. Dermatol. 134:S121?Abstract 693. TIGIT blockade may be effective in enhancing anti-tumor CD8+ T cells response to tumors when there is co-activating receptor DNAM-1CD226, which competes for binding to PVR/CD155. Some experiments show this. Johnston et al. (2014) Cancer Cell 26.1-15
Recent experiments showed that intratumoral bacteria expressing Fap2 protein could inhibit NK cell mediated tumour killing by binding with TIGIT (Gur et. al. (2015) Immunity 42, 344. This suggests that eliminating such bacteria and blocking TIGIT’s interaction with Fap2 or the activity of TIGIT overall may be helpful in the treatment of cancer. colorectal cancer. Hampton (2015) JAMA 333, 1305
There is a need for better methods to treat cancer and chronic viral infections. There are also medicaments such as therapeutic monoclonal antibody therapies that can be used in these methods. These medicines may contain antibodies or fragments of antibodies that specifically bind TIGIT to reverse or partially reverse TIGIT-mediated suppression or anti-viral immune reactions.
The present invention provides improved treatments and methods for chronic viral infections and cancer. It includes antibodies or antigen-binding fragments of antibodies that bind to the huTIGIT. Isolated antibodies, including monoclonal antibodies from humans, are provided herein that bind specifically to huTIGIT. They also have desirable functional properties such as binding to TIGIT to PVR or Nectin-2, blocking TIGIT interaction with DNAM and/or blocking binding to TIGIT to Nectin-2.
The present invention also provides better methods for treating cancer and therapeutic antibody to use in those methods. This includes tumors where TIGIT-mediated signaling suppresses the anti-tumor immunity response. It also covers tumors in tumors that TIGIT-expressing regulatory T cell suppress the anti-tumor immuno response. The invention provides therapeutic antibodies and methods for treating chronic viral infections where TIGIT suppresses the anti-viral immune response.
Another aspect of the invention is that the present invention pertains to antibodies that compete for the antibodies having heavy or light chain variable sequences in the disclosed herein to bind to huTIGIT and/or that block the binding of the heavy and light chains variable sequences in the disclosed herein to huTIGIT.
In certain embodiments the anti-TIGIT antibody of the present invention or antigen binding fragments thereof enhance an anti-tumor immuno response, e.g. an antigen-specific T cell response. Other embodiments of the invention’s anti-TIGIT antibody, or antigen-binding fragments thereof, block TIGIT mediated inhibitory signals. This allows PVR/DNAM costimulation of NK cell to increase NK-mediated antitumor response killing. Another embodiment of the anti-TIGIT antibody or antigen-binding fragments of the invention depletes a population regulatory T cells in a tumor, which would otherwise suppress the anti-tumor immunity response. Another embodiment of the anti-TIGIT antibody of the present invention, formatted as IgG1s, depletes CD8+ exhausted T cell and Tregs. This allows for the infusion of fresh, non-exhausted, CD8+ T cells. Other embodiments of the anti-TIGIT antibody of the present invention or antigen binding fragments thereof act via one or more of the mentioned mechanisms, since they are not always mutually exclusive.
Anti-TIGIT antibodies or antigen binding fragments of the present invention do not bind with activating Fc in certain embodiments. Fc?Rs, e.g. In embodiments that rely on increasing the anti-tumor activity in TIGIT-expressing cell, Alternate embodiments of the invention include anti-TIGIT antibodies or antigen binding fragments that bind to one or several activating Fc??Rs. In embodiments that rely on the killing of TIGIT-expressing cell types, such as tired CD8+ T cells and Tregs,
The present invention also contains isolated monoclonal antibody (15A6) or antigen binding fragments thereof that bind specifically to huTIGIT. They comprise heavy chain CDRH1, CDRH2, CDRH3 and CDRH3 sequences consisting of SEQ ID Nos: 14, 15, and 16, respectively and/or light-chain CDRL1, CDRL2, CDRL3, and CDRL3 sequences consisting of SEQ ID nos: 17, 18 and 19.
The present invention also contains monoclonal antibodies (22G2) or antigen binding fragments thereof that bind specifically to huTIGIT. They are heavy chain CDRH1, CDRH2, CDRH3, and CDRH3 sequences consisting of SEQ ID Nos: 20, 21, and 22, respectively and/or light-chain CDRL1, CDRL2, CDRL3, and CDRL3 sequences consisting of SEQ ID Ns: 23, 24 and 25, respectively.
The present invention also provides monoclonal monoclonal antibodies (11G11), and antigen binding fragments thereof that specifically binds to huTIGIT. They comprise heavy chain CDRH1, CDRH2, CDRH3, and CDRH3 sequences comprising respective SEQ ID Nos: 26, 27, and 28, respectively, as well as light chain CDRL1, CDRL2, or CDRL3 sequences comprising respective SEQ ID nos: 29, 30 and 31.
The invention also provides monoclonal antibodies (10D7) or antigen binding fragments thereof that specifically binds to huTIGIT. They comprise heavy chain CDRH1, CDRH2, CDRH3 and CDRH3 sequences consisting of SEQ ID Nos 32, 33, and 34, respectively and/or light-chain CDRL1, CDRL2, CDRL3, and CDRL3 sequences consisting of SEQ ID nos 35, 36 and 37, respectively.
The present invention provides monoclonal monoclonal antibodies or antigen binding fragments that bind specifically to huTIGIT. They include the variable heavy chain and light chain sequences disclosed at SEQID NOs 2 (or 3, 4, 5) and 6, SEQID NOs 7 (or 8 ) and 9, SEQID NOs 10 (or 11), and SEQID NOs 12 and 13.
The present invention contains monoclonal monoclonal antibodies or antigen binding fragments that bind to HuTIGIT. The heavy chain variable regions of the heavy chain include an amino acid sequence at least 90%, 95%, or 99% identical with the sequence chosen from the SEQ ID NOs 2, 3, 4, 5, 7, 8 and 12.
The present invention provides monoclonal antibodies or antigen binding fragments that bind to human huTIGIT, and also includes heavy and light-chain variable regions. The light chain variable region contains an amino acid sequence at least 90%, 95%, or 99% identical with the sequence chosen from the SEQ ID NOs 6, 9, 11 and 13.
In some embodiments, the monoclonal antibodies or antigen binding fragments of the present invention (a) bind the same epitope as 15A6, 22,G2, 11G11 and/or10D7 and/or (b), inhibit binding of 15A6, 22,G2, 11G11 and/or10D7 to huTIGIT (measured, e.g. by FACS/ELISA).
Anti-huTIGIT antibodies, or antigen-binding fragments thereof, may bind to certain epitopes comprising one or more residues of E60 or I109, L65 or N70 or F107 or T117 or I68 or H76 (antibody 22G2)) or an epitope consisting or comprising one or several residues of G74 or L65 or N58, Q139 or G135, L73 or L73 or P114 (antibody 1G11), H76, E60 or H134, A132, H134, H134, I109 (antibody15A132, H134, A132, H134, I109 (antibody 15A6) (antibody 15A6).
Alternatively, the anti-huTIGIT antibodies of the present invention, or antigen binding fragments thereof, bind at an epitope comprising or consisting of one or more sequences selected from the group consisting of NWEQQDQLLAICNADLGWH (SEQ ID NO: 38) and FCIYHTYPDGT (SEQ ID NO: 39) (antibody 22G2), or from the group consisting of QVNWEQQDQLLAICNADLGWH (SEQ ID NO: 40) and HTYP (SEQ ID NO: 41) (antibody 11G11), or from the group consisting of NWEQQDQLLAICNADLGWH (SEQ ID NO: 38), FCI, and AEHGARFQ (SEQ ID NO: 43) (antibody 15A6).
In further embodiments, an anti-TIGIT antibody or antigen binding fragment of the present invention binds to a core epitope of huTIGIT (SEQID NO: 1) consisting or comprising one or more residues L65 or I68, N70 or H76 and/or at an epitope consisting or comprising of LLAICNADLGWH. (SEQID NO: 44).
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