Cell-Penetrating Antibodies to Oncogenic RAS Show Anti-Tumor Activity
The technology is being further developed by Orum Therapeutics
Daejeon, South Korea, May 10, 2017 – The RAS gene family are the most commonly mutated oncogenes, involved in approximately 30% of all human cancers, but have eluded drug discovery efforts for over 30 years. With data published today in Nature Communications, researchers have gotten one step closer to developing a drug that targets RAS.
RAS proteins function to transmit signals within cells that control cell growth, differentiation and survival, and mutations found in human cancers result in RAS being constitutively activated. In addition to playing a role in tumor formation, tumors containing activating RAS mutations are often aggressive and do not respond to current therapies, including drugs targeting EGFR such as cetuximab (Erbitux®). Despite its prominent role in human cancer, previous efforts to directly target activated RAS have failed to produce a therapy that works in humans.
“Discovered nearly 35 years ago, the mutant RAS protein has been considered a highly-validated cancer drug target, but also has a reputation as being undruggable,” said Yong Sung Kim, Ph.D., principle investigator on the paper, co-founder of Orum Therapeutics, and professor, Department of Molecular Science and Technology at Ajou University, Korea.
The paper published today by scientists at Ajou University and Orum Therapeutics describes the preclinical characterization of a novel monoclonal antibody, called RT11-i, designed to be internalized by the cell and to directly target the activated form of RAS. The data shows that RT11-i binding is specific to activated RAS, binds these proteins inside the cell and blocks interactions with effector proteins, and results in inhibition of downstream oncogenic signaling. When given to tumor-bearing mice, RT11-i inhibited tumor growth in several xenograft models and shown to be well tolerated.
Dr. Kim explained, “This data shows that with our cell penetrating antibody technology, we now have the ability to selectively inhibit activated RAS to achieve anti-tumor activity with a systemically administered monoclonal antibody. Additional data suggests the combination of RT11-i and an anti-EGFR therapy might be an effective clinical strategy for patients with advanced colon cancer who have oncogenic RAS mutations.”
When tested in xenograft models of human cancer, RT11-i had preferential accumulation in tumor tissue and demonstrated measureable anti-tumor activity in mice where the tumor contained an activating RAS mutation. In addition, in a xenograft mouse model of colorectal cancer resistant to cetuximab, which targets EGFR, co-adminstration of cetuximab and RT11-i was shown to overcome resistance to cetuximab.
“As an anti-cancer therapy, our cell penetrating antibodies are easy to produce, allow for systemic administration that is well tolerated, and have desirable pharmacological properties,” said Sung Joo Lee, Ph.D., Co-founder and CEO of Orum Therapeutics. “We believe this could be a very important first-in-class therapeutic for hard-to-treat pancreatic, colon and non-small cell lung cancers.”
The paper entitled, “Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumor effects after systemic administration,” was published online today in Nature Communications, and can be found here: https://www.nature.com/articles/ncomms15090.
This work was supported by grants from the Pioneer Research Center Program (2014M3C1A3051470) and the Global Frontier Project (2013M3A6A4043874) from the National Research Foundation (NRF), funded by the Republic of Korea.
About Orum Therapeutics, Inc.
Orum Therapeutics is a private biotech company developing a new class of therapeutic antibodies to bring new medicines to patients with unmet medical needs. Orum leverages its unique cell penetrating antibody platform to inhibit drug targets undruggable by small molecule or current antibody therapeutics. In contrast to other approaches, Orum’s antibody platform can target specific cell types, is easily adaptable to target different cell types and different intracellular proteins, and does not require chemical modification. This provides new opportunities to treat severe genetic diseases and cancer.