Anti-TIGIT Demonstrates Potent Anti-Tumor Activity in Preclinical Models
WASHINGTON, DC and REDWOOD CITY, CA, USA I April 03, 2017 I OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, presented data from multiple preclinical studies detailing the mechanism and anti-tumor activity of anti-TIGIT alone and in combination with checkpoint inhibitors at the AACR Annual Meeting 2017. These are the first data from OncoMed’s anti-TIGIT program to be shared publicly. OncoMed plans to initiate a Phase 1a single-agent study of its anti-TIGIT antibody (OMP-313M32) in the first half of 2017.
“TIGIT is a highly desirable target in immuno-oncology with similarities in structure and function to PD1 and broad expression of its ligands on a wide variety of tumor tissues. We believe that by blocking TIGIT signaling our anti-TIGIT antibody may enable T-cell activation and facilitate a potent anti-tumor immune response, potentially halting the growth and recurrence of tumors,” said Austin Gurney, Ph.D., OncoMed’s Senior Vice President of Molecular and Cellular Biology and co-Chief Scientific Officer. “In multiple preclinical studies with anti-TIGIT antibodies we have observed immune activation and robust anti-tumor activity — both as a single agent and in combination with other cancer immunotherapeutics. Notably, the effect on inhibiting tumor growth persists upon re-challenging cured animals with re-injection of tumor cells, indicating that we are inducing a long-term immune memory response that we hope will translate into long-term clinical benefit. We look forward to advancing our anti-TIGIT antibody into the clinic in the first half of 2017.”
Anti-TIGIT AACR Annual Meeting 2017 Highlights
Anti-TIGIT demonstrates single-agent activity in multiple models
TIGIT (T cell immune-receptor with Ig and ITIM domains) is an inhibitory checkpoint receptor that binds to PVR ligand, a protein broadly expressed on tumor cells and tumor-infiltrating cells, and, in doing so, blocks T-cell activation. In order to test the immune response and anti-tumor activity of anti-TIGIT, OncoMed researchers developed a surrogate TIGIT-blocking antibody that could be tested in syngeneic mouse models. Potent single-agent, dose-dependent anti-tumor efficacy was observed on large established tumors in multiple murine models, including colorectal, breast and melanoma. In a separate set of experiments using patient-derived xenograft models in humanized mice containing human lymphocytes derived from hematopoietic stem cells, anti-TIGIT inhibited human melanoma tumor growth.
Anti-TIGIT induces immune memory responses
In another set of experiments, the surrogate anti-TIGIT antibody inhibited the growth of kidney and colon tumors in immune-competent mice, causing complete tumor regression. When mice were re-challenged with the same tumor cells after having achieved complete regression, tumors did not regrow and the mice remained tumor free, indicating that single-agent anti-TIGIT induces powerful Th1-type immune memory response and increases cytotoxic lymphocyte activity.
Anti-TIGIT plus anti-PD1 or anti-PDL1 results in potent anti-tumor activity
Anti-TIGIT demonstrated combination activity when combined with checkpoint inhibitors anti-PD1 and anti-PDL1 in preclinical models. In colon cancer models, the combination inhibited tumor growth and resulted in complete rejection of the tumors, significantly increasing mice survival as compared to control or to anti-TIGIT, anti-PD1 or anti-PDL1 alone. Further, when mice whose tumors achieved complete regression following treatment with anti-TIGIT plus anti-PD1 or anti-TIGIT plus anti-PDL1 were re-challenged with increasing number of tumor cells, they remained protected from tumor growth, suggesting the induction of immunologic memory against the tumor cells.
Anti-TIGIT activates cytotoxic immune responses directed at tumors; pharmacodynamics markers identified going into the clinic
In vivo studies of anti-TIGIT’s anti-tumor activity provided insight into its mechanism of action. In preclinical studies, anti-TIGIT increased cytotoxic T-cell activity against tumor cells and decreased T-cell suppression. More specifically, anti-TIGIT promoted dose-dependent increases in T and NK cell activation in tumors, as well as increased infiltration of T cells into the tumor. Consistent with the mechanism of action, anti-TIGIT treatment promoted upregulation of immune genes associated with activation of T and NK cells, Th1 response and cytotoxic activity. Blood and tumor samples analyzing pharmacodynamic (PD) markers of immune responses were consistent, suggesting that blood may be a potential surrogate tissue for measuring PD markers of anti-TIGIT activity. Immunohistochemistry (IHC) profiling of a large human tumor panel including multiple indications showed the highest TIGIT expression on immune cells associated with tumors at varying levels, while it was generally low on tumor cells.
AACR Presentations
These data were presented in three posters during the American Association for Cancer Research (AACR) Annual Meeting in Washington, DC:
Title: “Pharmacodynamic biomarkers for anti-TIGIT treatment and prevalence of TIGIT expression in multiple solid tumor types“
Abstract: 599
Title: “Antibody against TIGIT (T-cell immunoreceptor with Ig and ITIM domains) induces anti-tumor immune response and generates long-term immune memory”
Abstract: 2003
Title: “Anti-TIGIT induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity“
Abstract: 2612
About Anti-TIGIT
TIGIT (T cell immunoreceptor with Ig and ITIM domains) blocks T cells from attacking tumor cells, similar to the inhibitory protein PD-1. OncoMed’s anti-TIGIT antibody (OMP-313M32) is intended to activate the immune system through multiple mechanisms and enable anti-tumor activity. A Phase I clinical trial of anti-TIGIT is expected to begin enrolling patients during the first half of 2017.
This program is part of OncoMed’s Celgene collaboration. Upon the completion of certain enrollment criteria in the Phase I clinical trial, Celgene will have the option to obtain an exclusive license to anti-TIGIT.
About OncoMed Pharmaceuticals
OncoMed Pharmaceuticals is a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics. OncoMed has internally discovered a broad pipeline of investigational drugs intended to address the fundamental biology driving cancer’s growth, resistance, recurrence and metastasis. Demcizumab (anti-DLL4, OMP-21M18), tarextumab (anti-Notch2/3, OMP-59R5), navicixizumab (anti-DLL4/VEGF bispecific, OMP-305B83), vantictumab (anti-FZD7, OMP-18R5), ipafricept (FZD8-Fc, OMP-54F28), anti-RSPO3 (OMP-131R10) and anti-TIGIT (OMP-313M32) are part of the company’s strategic alliances with Celgene Corporation, Bayer Pharma AG and GlaxoSmithKline (GSK). OncoMed is independently developing brontictuzumab (anti-Notch1, OMP-52M51) and GITRL-Fc (OMP-336B11), as well as continuing to pursue new drug discovery research efforts. For further information about OncoMed Pharmaceuticals, please see www.oncomed.com.
SOURCE: OncoMed Pharmaceuticals
Post Views: 107
Anti-TIGIT Demonstrates Potent Anti-Tumor Activity in Preclinical Models
WASHINGTON, DC and REDWOOD CITY, CA, USA I April 03, 2017 I OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics, presented data from multiple preclinical studies detailing the mechanism and anti-tumor activity of anti-TIGIT alone and in combination with checkpoint inhibitors at the AACR Annual Meeting 2017. These are the first data from OncoMed’s anti-TIGIT program to be shared publicly. OncoMed plans to initiate a Phase 1a single-agent study of its anti-TIGIT antibody (OMP-313M32) in the first half of 2017.
“TIGIT is a highly desirable target in immuno-oncology with similarities in structure and function to PD1 and broad expression of its ligands on a wide variety of tumor tissues. We believe that by blocking TIGIT signaling our anti-TIGIT antibody may enable T-cell activation and facilitate a potent anti-tumor immune response, potentially halting the growth and recurrence of tumors,” said Austin Gurney, Ph.D., OncoMed’s Senior Vice President of Molecular and Cellular Biology and co-Chief Scientific Officer. “In multiple preclinical studies with anti-TIGIT antibodies we have observed immune activation and robust anti-tumor activity — both as a single agent and in combination with other cancer immunotherapeutics. Notably, the effect on inhibiting tumor growth persists upon re-challenging cured animals with re-injection of tumor cells, indicating that we are inducing a long-term immune memory response that we hope will translate into long-term clinical benefit. We look forward to advancing our anti-TIGIT antibody into the clinic in the first half of 2017.”
Anti-TIGIT AACR Annual Meeting 2017 Highlights
Anti-TIGIT demonstrates single-agent activity in multiple models
TIGIT (T cell immune-receptor with Ig and ITIM domains) is an inhibitory checkpoint receptor that binds to PVR ligand, a protein broadly expressed on tumor cells and tumor-infiltrating cells, and, in doing so, blocks T-cell activation. In order to test the immune response and anti-tumor activity of anti-TIGIT, OncoMed researchers developed a surrogate TIGIT-blocking antibody that could be tested in syngeneic mouse models. Potent single-agent, dose-dependent anti-tumor efficacy was observed on large established tumors in multiple murine models, including colorectal, breast and melanoma. In a separate set of experiments using patient-derived xenograft models in humanized mice containing human lymphocytes derived from hematopoietic stem cells, anti-TIGIT inhibited human melanoma tumor growth.
Anti-TIGIT induces immune memory responses
In another set of experiments, the surrogate anti-TIGIT antibody inhibited the growth of kidney and colon tumors in immune-competent mice, causing complete tumor regression. When mice were re-challenged with the same tumor cells after having achieved complete regression, tumors did not regrow and the mice remained tumor free, indicating that single-agent anti-TIGIT induces powerful Th1-type immune memory response and increases cytotoxic lymphocyte activity.
Anti-TIGIT plus anti-PD1 or anti-PDL1 results in potent anti-tumor activity
Anti-TIGIT demonstrated combination activity when combined with checkpoint inhibitors anti-PD1 and anti-PDL1 in preclinical models. In colon cancer models, the combination inhibited tumor growth and resulted in complete rejection of the tumors, significantly increasing mice survival as compared to control or to anti-TIGIT, anti-PD1 or anti-PDL1 alone. Further, when mice whose tumors achieved complete regression following treatment with anti-TIGIT plus anti-PD1 or anti-TIGIT plus anti-PDL1 were re-challenged with increasing number of tumor cells, they remained protected from tumor growth, suggesting the induction of immunologic memory against the tumor cells.
Anti-TIGIT activates cytotoxic immune responses directed at tumors; pharmacodynamics markers identified going into the clinic
In vivo studies of anti-TIGIT’s anti-tumor activity provided insight into its mechanism of action. In preclinical studies, anti-TIGIT increased cytotoxic T-cell activity against tumor cells and decreased T-cell suppression. More specifically, anti-TIGIT promoted dose-dependent increases in T and NK cell activation in tumors, as well as increased infiltration of T cells into the tumor. Consistent with the mechanism of action, anti-TIGIT treatment promoted upregulation of immune genes associated with activation of T and NK cells, Th1 response and cytotoxic activity. Blood and tumor samples analyzing pharmacodynamic (PD) markers of immune responses were consistent, suggesting that blood may be a potential surrogate tissue for measuring PD markers of anti-TIGIT activity. Immunohistochemistry (IHC) profiling of a large human tumor panel including multiple indications showed the highest TIGIT expression on immune cells associated with tumors at varying levels, while it was generally low on tumor cells.
AACR Presentations
These data were presented in three posters during the American Association for Cancer Research (AACR) Annual Meeting in Washington, DC:
Title: “Pharmacodynamic biomarkers for anti-TIGIT treatment and prevalence of TIGIT expression in multiple solid tumor types“
Abstract: 599
Title: “Antibody against TIGIT (T-cell immunoreceptor with Ig and ITIM domains) induces anti-tumor immune response and generates long-term immune memory”
Abstract: 2003
Title: “Anti-TIGIT induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity“
Abstract: 2612
About Anti-TIGIT
TIGIT (T cell immunoreceptor with Ig and ITIM domains) blocks T cells from attacking tumor cells, similar to the inhibitory protein PD-1. OncoMed’s anti-TIGIT antibody (OMP-313M32) is intended to activate the immune system through multiple mechanisms and enable anti-tumor activity. A Phase I clinical trial of anti-TIGIT is expected to begin enrolling patients during the first half of 2017.
This program is part of OncoMed’s Celgene collaboration. Upon the completion of certain enrollment criteria in the Phase I clinical trial, Celgene will have the option to obtain an exclusive license to anti-TIGIT.
About OncoMed Pharmaceuticals
OncoMed Pharmaceuticals is a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics. OncoMed has internally discovered a broad pipeline of investigational drugs intended to address the fundamental biology driving cancer’s growth, resistance, recurrence and metastasis. Demcizumab (anti-DLL4, OMP-21M18), tarextumab (anti-Notch2/3, OMP-59R5), navicixizumab (anti-DLL4/VEGF bispecific, OMP-305B83), vantictumab (anti-FZD7, OMP-18R5), ipafricept (FZD8-Fc, OMP-54F28), anti-RSPO3 (OMP-131R10) and anti-TIGIT (OMP-313M32) are part of the company’s strategic alliances with Celgene Corporation, Bayer Pharma AG and GlaxoSmithKline (GSK). OncoMed is independently developing brontictuzumab (anti-Notch1, OMP-52M51) and GITRL-Fc (OMP-336B11), as well as continuing to pursue new drug discovery research efforts. For further information about OncoMed Pharmaceuticals, please see www.oncomed.com.
SOURCE: OncoMed Pharmaceuticals
Post Views: 107
