Since the U.S. Food and Drug Administration’s (FDA’s) initial approval of the anti-CD20 antibody rituximab in 1997 to treat relapsed or refractory low-grade B cell lymphomas, monoclonal antibodies have been a mainstay of therapy for many hematologic malignancies. On its own, rituximab facilitates apoptosis of the CD20-expressing cells; it also mediates antibody-dependent cellular cytotoxicity by engaging effector immune cells, including natural killer cells, to lyse the targeted tumor cells.
In the 22 years since rituximab’s approval, many monoclonal antibodies to treat both hematologic malignancies and solid tumor cancers have entered the market, including gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia, ofatumumab to target CD20 in patients with chronic lymphocytic leukemia (CLL), daratumumab to target CD38 in patients with multiple myeloma, and many others.
Using protein engineering tricks that became feasible only during the 1990s, researchers can now create multifunctional antibodies that bring together antibody fragments in novel ways to create so-called bispecific antibodies that have two targets instead of one. Furthermore, these bispecific antibodies can be made to scale for clinical production.1
“These agents target both malignant cells, based on the expression of a specific marker, and the patient’s own T cells, based on a T cell–specific marker,†explained Farhad Ravandi, MD, from the University of Texas MD Anderson Cancer Center, who has taken part in several clinical trials of bispecific antibodies. “The agent acts as a bridge bringing these T cells into proximity of malignant cells and activating the T cells to kill malignant cells. This is a very elegant form of immunotherapy.â€
ASH Clinical News spoke with Dr. Ravandi and other researchers and clinicians about the biology of bispecific antibodies, their advantages and disadvantages, and how these new drug entities are faring in the clinic.
Bispecific Antibodies 101
Monoclonal antibodies have two arms that each recognize the same target antigen. In contrast, bispecific antibodies are engineered hybrid molecules with two unique binding domains, each of which recognizes a unique target. The first type of bispecific antibody to reach the clinic is a bispecific T cell engager. Each arm of these antibodies consists of a single-chain variable fragment – an engineered fusion protein and not an actual fragment of an antibody. One fragment recognizes and binds to a tumor antigen while the other recognizes and binds to an antigen on a T cell or other effector immune cells that can kill tumor cells. The two binding domains are joined by a short, flexible linker peptide. Bispecific antibodies also can be designed to bind to other non–T cell immune cells.
Because antibodies are biologics, requiring that living cells assemble parts of the antibody correctly; an initial challenge in making bispecific antibodies was being able to incorporate antibody subunits from two different antibodies into a single, functional unit with a stable configuration. Cells can generate these dual molecules in any one of 10 configurations, of which only one is correct and fully functional.
To get around this issue, researchers at California-based pharmaceutical manufacturer Amgen, which has several bispecific antibodies under investigation, have engineered antibodies with positive and negative electric charges at certain parts of the structure to promote correct assembly. Subunits fit together only in certain configurations to create a functional molecule.2
“These drugs are exciting because they are the result of innovative protein and antibody engineering,†commented Charles Sentman, PhD, from the Geisel School of Medicine at Dartmouth University, where his lab develops bispecific antibodies and other forms of immunotherapy.
As of November 2019, the FDA has approved one bispecific antibody for the treatment of cancer: blinatumomab. The drug binds to CD3 on T cells and the CD19 antigen on tumor cells.
The drug entered phase I trials in 2001 for the treatment of patients with acute lymphocytic leukemia (ALL). Thirteen years later, the FDA granted marketing approval for the treatment of adults and children with relapsed or refractory B cell precursor ALL. That indication was expanded in 2018, through the accelerated approval pathway, to include patients with B cell precursor ALL whose disease is in remission but is positive for measurable residual disease (MRD).
T cells need both the antigen-specific signal for activation and a secondary signal, known as co-stimulation, that immune cells use to mount a fully effective immune response. A unique feature of bispecific T cell engagers, in contrast to the endogenous immune response or to chimeric antigen receptor (CAR) T cells, is that these molecules don’t appear to require a co-stimulation signal to activate T cells against tumors.
One theory of why bispecific antibodies may not require the co-stimulation signal for full T cell activation is that these molecules predominantly activate memory T cells, which require less stimulation to mount a cytotoxic antitumor response. The T cells are then able to cluster together more effectively, triggering the necessary signal.3
With bispecific antibodies, the addition of a costimulatory signal has the potential to boost antitumor activity, according to Paulina Velasquez, MD, from St. Jude Children’s Research Hospital in Memphis, Tennessee. “The field is exploring strategies that incorporate costimulatory molecules, including expression of one or more of the costimulatory molecules as part of the bispecific antibody,†Dr. Velasquez told ASH Clinical News. “I think that these additions could potentially make the T cell responses more robust and longer-lasting.â€
Advantages of a Bispecific Molecule
There are more than a dozen bispecific antibodies for cancer treatment in clinical trials. One of the draws of these immune system–targeting molecules is that, unlike the customized CAR T cell therapies that take weeks to prepare for an individual patient, bispecific antibodies are off-the-shelf products.
“Ultimately, more patients will likely benefit from bispecific antibodies than CAR T cell therapies because they’re just so much easier to use,†said Max Topp, MD, from the University Hospital of Würzburg in Germany, who has taken part in clinical trials of blinatumomab and other bispecific antibodies. Still, Dr. Topp said, bispecific antibodies have some disadvantages related to administration. For example, blinatumomab has a short half-life and requires that the drug is given to patients by a continuous intravenous infusion using a pump, sometimes for longer than seven days at a time. “This can be quite cumbersome for patients,†he noted.
Another advantage of a bispecific antibody such as blinatumomab, according to Dr. Sentman, is its multifaceted ability to stimulate the adaptive arm of the immune response. The antibody engages and activates T cells, which then further triggers the release of cytokines that attract additional immune cells, including macrophages and natural killer cells, to target the tumor.