Astellas Pharma Inc. (Tokyo, Japan) and The University of Texas MD Anderson Cancer Center (Houston, Texas) have signed an option agreement to research and develop a new treatment for patients with acute myeloid leukemia (AML).

The collaboration gives Astellas an option to firstly negotiate an exclusive, worldwide license at the end of Phase Ib, with both Phase Ia and Phase Ib studies which will be conducted by MD Anderson. The parties also included up to $26 million as an option premium and research and development funding.

Jeffrey J. Molldrem, M.D. – Professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX. He is also Chief, Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, UT MD Anderson Cancer Center, Houston, TX.

Acute myeloid leukemia
While acute myeloid leukemias are infrequent, they are highly malignant neoplasms responsible for a large number of cancer-related deaths. According to the American Cancer Society, acute leukemias accounts for <3% of all cancers, these diseases constitute the leading cause of death due to cancer in children and persons age <39 years.[1]

The disease generally shows 2 peaks in occurrence in early childhood and later adulthood. With an incidence of 3.7 per 100,000 persons and an age-dependent mortality between 2.7 to 18 per 100,000 persons, there is a rising awareness of the disease in the Western world.[1]

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A new BiTe against acute myeloid leukemia
Jeffrey J. Molldrem, M.D., professor of Stem Cell Transplantation and Cellular Therapy at MD Anderson Cancer Center, Houston, TX and a team of researchers have discovered PR1 as an effective human leukocyte antigen (HLA)-A2 restricted peptide and, in clinical trials have targeted it using PR1 peptide vaccine.  Molder’s research has shown PR1 to be immunogenic in myeloid malignancies,  Based on these results, the researchers started developing several PR1 targeting therapies.

As part of their research, the team developed a humanization of a T-cell receptor-like monoclonal antibody (h8F4) that targets PR1/HLA-A2 and eliminates primary human AML xenografts in NOD scid gamma (NSG) mice. To improve the efficacy of h8F4, they also developed a bi-specific T-cell engaging (BiTE) antibody that targets leukemia PR1/HLA-A2 and the T-cell receptor CD3.

The initial results showed that h8F4 BiTE binds endogenous PR1 on several commonly used AML cell lines and that these cell lines are able to activate PBMC via h8F4 BiTE engagement.

The researchers believe that because h8F4 targets the HLA-restricted peptide PR1/HLA-A2, which is expressed in cancer cells and cancer stem cells, this novel BiTE antibody could potentially provide a safer and more potent treatment option for patients with aggressive myeloid leukemias that will improve upon currently available highly toxic standard therapies.

Carlo Toniatti MD, Ph.D, is Head of Research of the Institute for Applied Cancer Science , drug discovery and clinical development in both a biotech and a pharmaceutical company environment. Toniatti has substantial expertise in oncology and also in gene therapy and RNA- interference, recombinant growth factors and transcriptional regulation.
Toniatti received an M.D. degree at the University of Naples, Italy and a Ph.D. in Molecular and Cellular Biology and Pathology at the University of Naples, Italy.

Focusing on h8F4
The collaboration between Astellas and MD Anderson focuses on h8F4 technology. Molldrem will lead these research efforts with Carlo Toniatti, M.D., Ph.D., executive director of MD Anderson’s Oncology Research for Biologics and Immunotherapy Translation (ORBIT) platform.

“Current treatments for aggressive leukemias are often toxic,” Molldrem noted. “We desired to develop a safer, yet more potent, therapy for these aggressive cancer types that currently have poor survival outcomes. Unfortunately, advancing novel discoveries from the laboratory to drug development has been historically challenging. We hope that this important collaboration will allow us to deliver much-needed antibody-based treatment to the patient’s bedside more quickly.”

“h8F4 has a radically novel anti-tumor activity and this collaboration provides MD Anderson and Astellas with a great opportunity to potentially deliver a first-in-class antibody drug to patients with AML,” commented Yoshihiko Hatanaka, president and CEO of Astellas. “Astellas continues to focus on developing novel therapies in areas of unmet medical need through in-house developments and external collaborations.”

While monoclonal antibodies are very common in oncology, generating antibodies against HLA-restricted peptides has proven difficult. To develop viable antibody drugs, MD Anderson created ORBIT for its Moon Shots Program, to centralize this type of research. The program is an ambitious initiative to accelerate the conversion of innovative scientific discoveries into clinical advances and significantly reduce cancer deaths. The program is fueled by exceptionally broad collaborations and underpinned by state-of-the-art resources. Researchers expect that with the discovery of new paths to prevention, early detection and treatment of cancers, new ways to reshape the way all other cancers are attacked will come to light.

“This is an outstanding addition to MD Anderson’s Moon Shots Program to deliver accelerated solutions for cancer treatment,” said Ronald DePinho, M.D., president of MD Anderson. “These are exciting times for cancer drug development and I’m proud that eminent scientists like Molldrem and Toniatti are leading the way. While it’s true that myeloid cancer has not responded well to standard therapies, this novel solution looks promising.”

Other MD Anderson Moon Shot programs focusing on cancers that are especially lethal, include lung cancer, leukemias (CLL, MDS-AML), triple-negative breast cancer, high-grade serous ovarian cancer, prostate cancer and melanoma. Earlier this year The University of Texas MD Anderson Cancer Center and announced a multiyear research collaboration with AstraZeneca to conduct multiple, parallel clinical and clinically related studies in ovarian and other gynecologic cancers.[2]

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