Bispecific antibodies that mirror the natural biology of immune T-cells are the key to a new generation of cancer therapies, according to Regeneron.
Antibodies bind specific antigens – molecular targets such as proteins expressed on the surface of tumors. Bispecific antibodies, as the name suggests, can bind two antigens at the same time.
This binding ability means they have significant potential as therapies according to Eric Smith, senior director of bispecific antibodies at Regeneron, who shared details of the firm’s research at the Antibody Engineering and Therapeutics conference in San Diego, late last year.
“What we’re really trying to achieve with these molecules is to mirror the natural biology of T-cell engagement, which as you’ve heard consists of signal one and signal two.”
In natural T-cell engagement signal one (activation) occurs when the TCR interacts with the major histocompatibility complex (MHC) on the tumor. Signal two (the co-stimulatory signal) happens when molecules like the T-cell receptor CD28 bind ligands presented on cancer cells.
“It turns out we can actually mirror both of these signals artificially using bispecifics […] leading to a more natural-like engagement of your T-cell response” Smith said.
This ability to mimic natural T-cell engagement has real therapeutic potential Smith said, explaining one strategy is to use bispecifics in combination with checkpoint inhibitors — drugs that target proteins cancers use to damp down the immune response.
“Regeneron has a PD1 inhibitor, Libtayo, that can inhibit this checkpoint. And we think that in combination with these other types of strategies that will lead to more potent T cell activation.”
The firm is using two broad approaches for the bispecific-checkpoint inhibitor combination strategy according to Smith, who said “the first is to use a pre-existing tumor reactive T Cell that would already be in the patient that has a natural signal.
“The other strategy is to combine CD-28 [targeting T Cells] with CD-3 bispecifics. We have several different programs underway, or soon to be underway, combining these,” he continued.
But combination therapy is not the only potential use of bispecific antibodies. Regeneron is also working on a new class of molecules that target “peptide-in-groove” bispecifics, or PIGs, which are short peptides that are only expressed on cancer cells.
“With all types of bispecifics it is really very important to have very good targets… otherwise you can get normal tissue expression and that can lead toxicities.
“So the idea is to explore the intracellular target space in terms of tumor specific mutations [to find proteins] that are only expressed on the surface of cancer cells.