Building on Today’s Science to Research Medicines of Tomorrow

May 12, 2020

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s a scientific research community, our work is never done for cancer patients. Building upon established science allows researchers to pursue new approaches, test new hypotheses and – ultimately – uncover new answers to emerging and enduring questions that may address unmet needs for patients. Below are just two examples of the research Bristol Myers Squibb is elevating to advance next-generation approaches in oncology and hematology. 

Building on CTLA-4 Expertise to Pursue New Approaches

Research into CTLA-4, an important immune checkpoint, has revolutionized the way some cancers are treated. Dr. Jim Allison’s Nobel Prize-winning discovery of the important role of CTLA-4 in cancer – taking the “brake” off a patient’s T-cells, enabling them to attack tumors – ultimately led to multiple approved immune checkpoint inhibitors.

Lee James, Senior Early Development Program Lead, Oncology, Bristol Myers Squibb

Today, there are nearly two decades of research into this class of drugs further validating the impact of CTLA-4 inhibition alone and in combination with other checkpoint inhibitors for multiple cancer types.

“We know that blocking CTLA-4 has proven to be effective, and there is a lot of opportunity to continue exploring CTLA-4 inhibition and new ways that it can be leveraged,” says Lee James, senior early development program lead, oncology, Bristol Myers Squibb. “Bristol Myers Squibb is uniquely positioned to tackle these questions – as an early collaborator of Dr. Allison’s and one of the first companies to advance this science, our CTLA-4 story is truly differentiated in the field."

To this end, Bristol Myers Squibb is exploring two strategies, each building on the existing CTLA-4 science through second generation and next generation compounds, with a goal of optimizing the risk-benefit profile of CTLA-4-directed therapy.

First, through a partnership with CytomX, Bristol Myers Squibb is investigating the use of Probody® technology, which may enable CTLA-4 antibodies to more effectively localize treatment to cancerous regions by exploiting the unique conditions found within the tumor microenvironment, all while hopefully limiting therapeutic activity in healthy tissues.

Separately, researchers are evaluating a non-fucosylated approach in CTLA-4 inhibition. Traditionally, non-fucosylated antibodies have been shown to be potentially efficacious and are likely less immunogenic (causing unwanted immune response), as their structure more closely resembles a normal component found in humans.

Beyond next-generation approaches, scientists are also expanding upon the strength of CTLA-4 inhibition by looking at several different tumor types and evaluating new lines of therapy.

“We know there is additional work to be done with CTLA-4,” says James. “We are continuing to better understand the ways that CTLA-4 can be used in certain tumor types, certain lines of therapy or other combinations, all building on our existing work in CTLA-4 inhibition to push research forward.”

Drugging the “Undruggable” Through Protein Degradation  

Maintaining an intricate balance of proteins, also known as protein homeostasis, is essential for human health. The ubiquitin-proteasome system (UPS) is one way the body naturally removes proteins, “tagging” them for degradation to maintain homeostasis. Bristol Myers Squibb’s – then Celgene’s – investigation of the UPS and protein homeostasis began more than two decades ago with research on its first IMiD® compounds, an important treatment class for hematologic cancers.  

Mark Rolfe, Senior Vice President Oncogenesis, Bristol Myers Squibb

Over time, continued research in the lab uncovered that an E-3 ligase called cereblon – one of about 600 proteins in the cell involved in the “tagging” system – plays an important role in the mechanisms of action for IMiDs®. Through this research, scientists realized the potential to degrade several whole new classes of proteins that were previously considered “undruggable,” an approach that was unimaginable even five years ago.

“We’ve realized we can degrade hundreds of previously unrecognized proteins, and this number is the tip of the iceberg – there is potentially the ability to target perhaps thousands of protein targets,” says Mark Rolfe, senior vice president, oncogenesis, Bristol Myers Squibb. “We’ve just scratched the surface when it comes to understanding how many proteins we can target, and our job now is to figure out which have therapeutic utility.”

Building on these learnings, researchers at Bristol Myers Squibb are studying novel CELMoD® (Cereblon E3 Ligase Modulation Drugs) agents that may potentially address a broader range of diseases, alone or in combination with other agents. CELMoDs are being investigated in different types of blood cancers such as multiple myeloma and acute myeloid leukemia (AML), as well as solid tumors and immune-mediated diseases like lupus.

“The opportunity here is to open up the currently inaccessible solid tumor space to define proteins that are important for solid tumor survival and determine whether they can be degraded using this same approach,” Rolfe says. “This is a completely novel approach in the field, and we’re excited to better understand the impact it could have for patients living with solid tumors and beyond.”

Building from the legacy of research in oncology and hematology, today, Bristol Myers Squibb researchers look toward what’s next, working to discover and develop the next generation of therapies to deliver on our mission of transforming patients’ lives through science.

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