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Anti-tigit antibodies

a technology of anti-tigit antibodies and antibodies, which is applied in the field of anti-tigit antibodies, can solve the problems of poor prognosis, and the overexpression of pd-l1 in tumors, and achieve the effects of stimulating antigen-specific t-cell production, and reducing tumor specific t cell exhaustion

Inactive Publication Date: 2017-07-13
MERCK SHARP & DOHME CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a way to make an anti-TIGIT antibody that has better ability to fight tumors. This is done by modifying the antibody in a way that enhances its effectiveness. This can be done by changing parts of the antibody or by altering the way it is produced in a cell. The result is an anti-TIGIT antibody that is more effective at fighting tumors than the original version.

Problems solved by technology

Notably, overexpression of PD-L1 in tumors is associated with tumor specific T cell exhaustion and a poor prognosis.

Method used

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Examples

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example 1

Generation of Rat and Mouse Anti-hTIGIT Antibodies

[0370]To generate antibodies to human TIGIT, Lewis rats were immunized with his-tagged human TIGIT recombinant protein from Sino Biologicals Cat#10917-H08H) using RIBI adjuvant and footpad injection on a biweekly schedule. Alternatively, Balb / C mice were immunized with human Fc-tagged human TIGIT recombinant protein using RIBI adjuvant and footpad injection on a biweekly schedule. Immunized animals were bled and serum titers determined for binding to human TIGIT transfected CHOK1 cells using a cell-based ELISA (described below). The animals with the highest titers were given a final boost with recombinant protein and draining popliteal lymph nodes isolated four days later. Hybridomas were generated by electrofusion of isolated lymphocytes with the myeloma fusion partner P3X63-AG8.653 using the Cytopulse Hybrimmune electrofusion system. Fused cells were plated in 96-well plates in DMEM / F12, 15% BCS, HAT, IL-6, OPI supplement, and gent...

example 2

Characterization of Anti-hTIGIT Antibodies

[0374]Supernatants from positive clones were tested for their ability to block recombinant human CD155-huFc protein binding to hTIGIT CHOK1 cells in a cell-based ELISA format. Human TIGIT-CHO-K1 cells were plated in 96-well plates as described above. Media was removed from the plates and 50 μl of hybridoma supernatant was incubated with the human TIGIT CHO-K1 cells at 4° C. for 30 minutes. Fifty microliters of human CD155-huFc was added to the plate for a final concentration of 0.5 μg / ml of human CD155-huFc and incubated for 30 minutes at 4° C. Assay plates were washed 3 times with PBS / 0.05% Tween-20 as above. Binding of human CD155-huFc to the hTIGIT-CHOK1 cells was detected using an HRP-conjugate F(ab)′2 goat anti-human IgG secondary antibody (Jackson 109-036-098) at 1:2000 dilution in CHO-K1 media. Plates were developed using TMB and stopped using TMB Stop Solution as described above and the A450-620 nm determined.

[0375]A rat antibody gen...

example 3

In Vitro T-Cell Activity Assay for Antagonistic Anti-hTIGIT Antibodies

[0381]Of the antibodies tested, approximately 352 monoclonal antibodies shown to block binding of CD155-Fc to CHO cells expressing hTIGIT were screened for their capacity enhance T cell activity in vitro using cell-based functional assays.

[0382]One assay we developed to characterize the functional consequence of blocking human TIGIT receptor utilized Jurkat cells, an immortalized line of human T lymphocyte cells (clone, E6-1; ATCC TIB-152) engineered to over-express human TIGIT (hTIGIT-Jurkat) which were co-cultured with THP-1 cells, a human monocytic cell line in the presence or absence of one of the TIGIT ligands, CD155 and CD112. hTIGIT-Jurkat cells co-cultured with THP-1 cells and stimulated with plate-bound anti-CD3 mAb produce IL-2, but when TIGIT ligand (CD155 or CD112) is added to the co-culture, IL-2 levels were reduced in a ligand-dependent manner. Treatment with antibodies that blocked the CD155- or CD1...

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Abstract

The present invention relates to anti-TIGIT antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease.

Description

FIELD OF THE INVENTION[0001]The present invention relates to anti-TIGIT antibodies, as well as use of these antibodies in the treatment of diseases such as cancer and infectious disease.BACKGROUND OF THE INVENTION[0002]A key factor for enabling tumor immunotherapy emerged from discoveries that inhibitory immune modulatory receptors (IMRs), that generally function as immune checkpoints to maintain self-tolerance, are central to the ability of tumor microenvironments to evade immunity. Blockade of inhibitory IMRs appears to unleash potent tumor-specific immune responses more effectively than direct stimulation of tumor-immunity with activating cytokines or tumor vaccines, and this approach has the potential to transform human cancer therapy. An important implication and opportunity now arises for the potential to develop new antibody antagonists for other IMRs and to combine antagonist antibodies to more than one IMR in order to increase the proportion of responders in oncology clinic...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61K45/06A61K39/395
CPCC07K16/2803C07K16/2818A61K39/3955A61K45/06C07K2317/565A61K2039/507C07K2317/92C07K2317/24C07K2317/52C07K2317/76C07K2317/56C07K16/28A61K2039/505C07K2317/34C07K2317/21C07K2317/74A61P31/00A61P35/00A61P37/02A61P37/04A61P43/00Y02A50/30C07K2317/73A61K39/39541
Inventor WILLIAMS, SYBIL M. G.LAFACE, DRAKEFAYADAT-DILMAN, LAURENCERAGHUNATHAN, GOPALANLIANG, LINDASEGHEZZI, WOLFGANG
Owner MERCK SHARP & DOHME CORP
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