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 and broadening the understanding of its mechanism.
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. Preclinical data indicate that limiting antibody binding to the tumor microenvironment may prevent the immune system from attacking healthy cells, yet still enable an antitumor response.
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. Poor prognosis in various cancers is associated with the presence of regulatory T cells, and preclinical models have shown that a non-fucosylated anti-CTLA-4 approach can improve cytotoxic T cell activation and antitumor activity.
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.