Antibody-drug conjugate may provide new treatment option for pancreatic cancer patients

PUBLIC RELEASE DATE:

21-Oct-2013

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Contact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research

BOSTON Patients with pancreatic cancer may benefit from an investigational member of an emerging class of anticancer drugs called antibody-drug conjugates, according to preclinical results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.

Antibody-drug conjugates are a new type of targeted anticancer therapy, which use an antibody to deliver an attached drug directly to those cells that display the antibody's target on their surfaces. This precision reduces the side effects of the attached drug compared with conventional systemic administration. Currently, there are two U.S. Food and Drug Administration-approved antibody-drug conjugates used for the treatment of certain cancers.

"Our investigational antibody-drug conjugate, MLN0264, is designed to selectively bring a highly potent cytotoxic payload to tumors that express guanyl cyclase C (GCC)," said Petter Veiby, global head of BioTherapeutics, Oncology DDU at Takeda Pharmaceuticals International Co. in Boston, Mass. "Our findings in preclinical pancreatic tumor models support the testing of MLN0264 in combination with gemcitabine in patients with advanced pancreatic cancer."

MLN0264 consists of the highly toxic agent monomethyl auristatin E (MMAE) attached to an antibody that recognizes GCC via a cleavable linker. When the antibody portion of the drug recognizes the protein GCC on tumor cells, the entire drug is taken up by the cells. Once inside the tumor cells, the linker that attaches MMAE to the antibody is severed, allowing the tumor cells to be exposed to the cytotoxic activity of MMAE.

According to Veiby, at least 50 percent of the pancreatic tumors he and his colleagues have examined express some level of GCC. They, therefore, investigated the activity of MLN0264 in preclinical models of pancreatic cancer that mimicked the various patterns of GCC expression observed in patient biopsies.

They found that MLN0264 markedly inhibited the growth of five of seven different human pancreatic tumors transplanted into mice.

Further analysis in two of the preclinical models, one in which MLN0264 had significantly inhibited tumor growth and one in which it had little effect, showed that a combination of MLN0264 and the traditional chemotherapy agent gemcitabine caused greater tumor shrinkage than either drug alone.

Based on their preclinical data, the researchers plan to investigate the activity of the combination of MLN0264 and gemcitabine in patients with GCC-expressing pancreatic cancer in a phase II study, which they hope will begin sometime in 2014. They are also evaluating the activity of MLN0264 in preclinical models of two other cancers known to frequently express GCC, metastatic colorectal cancer and gastric cancer.

###

Veiby is an employee of Takeda Pharmaceuticals International Co., which funded the study.

The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).

This research will be presented at a press conference entitled "Overcoming Resistance and Hard-to-treat Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 21 at 9 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:

• U.S./Canada (toll-free): 800-446-2782
  
• International (toll): 847-413-3235

To interview Petter Veiby, contact David Albaugh at david.albaugh@mpi.com or 617-444-4456. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.

About the National Cancer Institute

The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About the European Organisation for Research and Treatment of Cancer

The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.

EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org

Abstract Number: PR12/B194

Presenter: Petter Veiby

Title: MLN0264, an investigational, first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase C (GCC), demonstrates antitumor activity alone and in combination with gemcitabine in human pancreatic cancer xenograft models expressing GCC

Authors: Julie Zhang, Melissa Gallery, Tim Wyant, Brad Stringer, Mark Manfredi, Hadi Danaee, Petter Veiby. Millennium: the Takeda Oncology Company, Cambridge, MA

Background: MLN0264 consists of a fully human anti-GCC monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker (MMAE and linker technology licensed from Seattle Genetics). The transmembrane cell surface receptor GCC is expressed by ~95% of primary and metastatic colorectal cancer (mCRC) tumors. MLN0264 has shown selective binding and antitumor activity in mouse xenograft models of mCRC expressing GCC, and is currently being investigated in a phase 1 study in patients with advanced gastrointestinal malignancies. GCC is also expressed in subsets of pancreatic cancers. Further to the findings in mCRC, we investigated GCC expression in human pancreatic tumors and evaluated MLN0264 activity in mouse xenograft models of GCC-expressing human pancreatic cancer.

Methods: GCC expression in multiple human pancreatic cancer samples including tissue microarrays (TMAs) was evaluated by immunohistochemistry (IHC). For in vivo studies, 7 mouse xenograft primary human tumor explant (PHTX) models of pancreatic cancer were developed, including tumor tissue from patients with wild-type and mutant KRAS. Animals were treated when the tumor reached ~230 mm3. In single-agent studies, animals were administered vehicle, MMAE 0.135 mg/kg once weekly (QW), or MLN0264 3.75 or 7.5 mg/kg QW. In combination studies, animals received vehicle, or MLN0264 7.5 mg/kg QW alone or in combination with gemcitabine 15 or 20 mg/kg twice weekly (BIW), or gemcitabine 15 mg/kg on days 1, 3 each week. Average tumor volume was determined at multiple time points following the start of treatment using vernier calipers.

Results: In the GCC-expressing PHTX-249 mouse xenograft model (KRAS mutant G12), single-agent MLN0264 showed significant tumor growth inhibition (TGI) versus vehicle or free MMAE by day 21, with the 7.5 mg/kg dose significantly better than 3.75 mg/kg by day 20-22. Similarly, in the GCC-expressing PHTX-215 model (KRAS wild-type), MLN0264 7.5 mg/kg resulted in significantly greater TGI (79%) versus free MMAE or MLN0264 3.75 mg/kg by day 22, including some tumor regression. Across the 7 models (variable apical GCC expression; KRAS wild-type and mutant), TGI ranged from 24% (p=0.17) to 79% (p

Conclusions: These findings indicate that MLN0264 has antitumor activity as a single agent and in combination with gemcitabine in GCC-expressing pancreatic cancer xenograft models, and support clinical evaluation of MLN0264 in patients with pancreatic cancer. Data from additional models will be presented.

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

PUBLIC RELEASE DATE:

21-Oct-2013

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Contact: Lauren Riley
lauren.riley@aacr.org
215-446-7155
American Association for Cancer Research

BOSTON Patients with pancreatic cancer may benefit from an investigational member of an emerging class of anticancer drugs called antibody-drug conjugates, according to preclinical results presented here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.

Antibody-drug conjugates are a new type of targeted anticancer therapy, which use an antibody to deliver an attached drug directly to those cells that display the antibody's target on their surfaces. This precision reduces the side effects of the attached drug compared with conventional systemic administration. Currently, there are two U.S. Food and Drug Administration-approved antibody-drug conjugates used for the treatment of certain cancers.

"Our investigational antibody-drug conjugate, MLN0264, is designed to selectively bring a highly potent cytotoxic payload to tumors that express guanyl cyclase C (GCC)," said Petter Veiby, global head of BioTherapeutics, Oncology DDU at Takeda Pharmaceuticals International Co. in Boston, Mass. "Our findings in preclinical pancreatic tumor models support the testing of MLN0264 in combination with gemcitabine in patients with advanced pancreatic cancer."

MLN0264 consists of the highly toxic agent monomethyl auristatin E (MMAE) attached to an antibody that recognizes GCC via a cleavable linker. When the antibody portion of the drug recognizes the protein GCC on tumor cells, the entire drug is taken up by the cells. Once inside the tumor cells, the linker that attaches MMAE to the antibody is severed, allowing the tumor cells to be exposed to the cytotoxic activity of MMAE.

According to Veiby, at least 50 percent of the pancreatic tumors he and his colleagues have examined express some level of GCC. They, therefore, investigated the activity of MLN0264 in preclinical models of pancreatic cancer that mimicked the various patterns of GCC expression observed in patient biopsies.

They found that MLN0264 markedly inhibited the growth of five of seven different human pancreatic tumors transplanted into mice.

Further analysis in two of the preclinical models, one in which MLN0264 had significantly inhibited tumor growth and one in which it had little effect, showed that a combination of MLN0264 and the traditional chemotherapy agent gemcitabine caused greater tumor shrinkage than either drug alone.

Based on their preclinical data, the researchers plan to investigate the activity of the combination of MLN0264 and gemcitabine in patients with GCC-expressing pancreatic cancer in a phase II study, which they hope will begin sometime in 2014. They are also evaluating the activity of MLN0264 in preclinical models of two other cancers known to frequently express GCC, metastatic colorectal cancer and gastric cancer.

###

Veiby is an employee of Takeda Pharmaceuticals International Co., which funded the study.

The 2013 International Conference on Molecular Targets and Cancer Therapeutics is being co-hosted by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).

This research will be presented at a press conference entitled "Overcoming Resistance and Hard-to-treat Cancers" during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on Monday, Oct. 21 at 9 a.m. ET in room 202 of the Hynes Convention Center in Boston, Mass. Reporters who cannot attend in person may call in using the following numbers:

• U.S./Canada (toll-free): 800-446-2782
  
• International (toll): 847-413-3235

To interview Petter Veiby, contact David Albaugh at david.albaugh@mpi.com or 617-444-4456. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.

About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org. Follow the AACR on Twitter: @AACR. Follow the AACR on Facebook: http://www.facebook.com/aacr.org.

About the National Cancer Institute

The National Cancer Institute (NCI) leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About the European Organisation for Research and Treatment of Cancer

The European Organisation for the Research and Treatment of Cancer (EORTC) brings together European cancer clinical research experts from all disciplines for trans-national collaboration. Both multinational and multidisciplinary, the EORTC Network comprises more than 2,500 collaborators from all disciplines involved in cancer treatment and research in more than 300 hospitals in over 30 countries. Through translational and clinical research, the EORTC offers an integrated approach to drug development, drug evaluation programs and medical practices.

EORTC Headquarters, a unique pan European clinical research infrastructure, is based in Brussels, Belgium, from where its various activities are coordinated and run. http://www.eortc.org

Abstract Number: PR12/B194

Presenter: Petter Veiby

Title: MLN0264, an investigational, first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase C (GCC), demonstrates antitumor activity alone and in combination with gemcitabine in human pancreatic cancer xenograft models expressing GCC

Authors: Julie Zhang, Melissa Gallery, Tim Wyant, Brad Stringer, Mark Manfredi, Hadi Danaee, Petter Veiby. Millennium: the Takeda Oncology Company, Cambridge, MA

Background: MLN0264 consists of a fully human anti-GCC monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker (MMAE and linker technology licensed from Seattle Genetics). The transmembrane cell surface receptor GCC is expressed by ~95% of primary and metastatic colorectal cancer (mCRC) tumors. MLN0264 has shown selective binding and antitumor activity in mouse xenograft models of mCRC expressing GCC, and is currently being investigated in a phase 1 study in patients with advanced gastrointestinal malignancies. GCC is also expressed in subsets of pancreatic cancers. Further to the findings in mCRC, we investigated GCC expression in human pancreatic tumors and evaluated MLN0264 activity in mouse xenograft models of GCC-expressing human pancreatic cancer.

Methods: GCC expression in multiple human pancreatic cancer samples including tissue microarrays (TMAs) was evaluated by immunohistochemistry (IHC). For in vivo studies, 7 mouse xenograft primary human tumor explant (PHTX) models of pancreatic cancer were developed, including tumor tissue from patients with wild-type and mutant KRAS. Animals were treated when the tumor reached ~230 mm3. In single-agent studies, animals were administered vehicle, MMAE 0.135 mg/kg once weekly (QW), or MLN0264 3.75 or 7.5 mg/kg QW. In combination studies, animals received vehicle, or MLN0264 7.5 mg/kg QW alone or in combination with gemcitabine 15 or 20 mg/kg twice weekly (BIW), or gemcitabine 15 mg/kg on days 1, 3 each week. Average tumor volume was determined at multiple time points following the start of treatment using vernier calipers.

Results: In the GCC-expressing PHTX-249 mouse xenograft model (KRAS mutant G12), single-agent MLN0264 showed significant tumor growth inhibition (TGI) versus vehicle or free MMAE by day 21, with the 7.5 mg/kg dose significantly better than 3.75 mg/kg by day 20-22. Similarly, in the GCC-expressing PHTX-215 model (KRAS wild-type), MLN0264 7.5 mg/kg resulted in significantly greater TGI (79%) versus free MMAE or MLN0264 3.75 mg/kg by day 22, including some tumor regression. Across the 7 models (variable apical GCC expression; KRAS wild-type and mutant), TGI ranged from 24% (p=0.17) to 79% (p

Conclusions: These findings indicate that MLN0264 has antitumor activity as a single agent and in combination with gemcitabine in GCC-expressing pancreatic cancer xenograft models, and support clinical evaluation of MLN0264 in patients with pancreatic cancer. Data from additional models will be presented.

---

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Source: http://www.eurekalert.org/pub_releases/2013-10/aafc-acm101513.php
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