As companies roll out data showing the power and improved safety profile of antibodies that target two antigens, analysts say the class could overtake monoclonal antibody Keytruda as the “immunotherapy backbone” of solid tumor treatment.
With Merck’s mega-blockbuster monoclonal antibody Keytruda set to lose exclusivity in 2028, another class of immunotherapy is waiting in the wings to take center stage in cancer treatment: bispecific antibodies with two separate targets.
“I think bispecifics are making a big comeback,” Mayank Mamtani, head of healthcare research at B.Riley Securities, told BioSpace prior to the 2024 European Society for Medical Oncology Congress, adding that the modality could supplant Keytruda as the “immunotherapy backbone of choice across many solid tumors.”
Bispecifics have drawn immense interest since the discovery of monoclonal antibodies (mAbs) in 1975. Development turned out to be challenging, however, and the first bispecific antibody (bsAb)—catumaxomab—was pulled from the U.S. market four years after its approval in 2013 for commercial reasons. A recent paper published in mAbs suggested this may have been due to administration restrictions—catumaxomab could only be administered intraperitoneally due to severe infusion reactions—and high immunogenicity. Only two more bispecific antibodies were approved between 2009 to 2020, but the pace has since picked up significantly. The FDA has green-lit nine bispecifics for cancer over the past three years.
With over 100 bispecifics in clinical development, several biopharma companies—including AstraZeneca, BioNTech and Summit Therapeutics—are hoping to jump on the comeback train.
Why a Bispecific Is Better Than a Drug Combo
Traditionally, combination drugs have meant giving “drug A” plus “drug B” to a patient at the same time. With a bispecific, A and B are part of the same molecule, offering benefits that stretch beyond manufacturing and patient convenience. It is proving safer and more powerful to pack them in together, said Ryan Schoenfeld, CEO of The Mark Foundation for Cancer Research.
One key feature, Schoenfeld told BioSpace, is specificity. “The drug only works when it meets both its targets, so you can fine-tune the selectivity.”
He estimated that around a third of cancer bispecifics are designed to bring immune cells into an environment they may otherwise not be trafficking. One side of the antibody anchors into the tumor while the other side attracts an immune cell to attack. This is particularly important in cold tumors, which are characterized by a lack of T cells and are often unresponsive to immunotherapy, Schoenfeld said.
While it’s relatively easy with immune stimulators to “turn up” a patient’s immunity, “that will lead to terrible side effects that won’t be tolerated,” Schoenfeld said. “Bispecific antibodies offer a very elegant solution to combination therapy . . . You’re ramping up immunity in a very specific region.”
In addition to the beneficial specificity, bispecifics also offer cooperative binding, John Heymach, chair of thoracic/head and neck oncology at MD Anderson Cancer Center, told BioSpace. The structure of these drugs promotes clustering, which leads to potent signaling for increased efficacy, he said.
AstraZeneca has been advancing a number of bispecific antibodies to overcome the challenges associated with the co-administration of drugs, such as dose-limiting toxicities. The company has also seen an efficacy benefit from the bispecific therapeutic design.
“The bispecifics’ nature allows for this cooperative, coordinated receptor binding,” Sunil Verma, SVP and global head of oncology, medical at AstraZeneca, told BioSpace. “As a result, we’re seeing greater T cell engagement and activation.”
With a Wealth of Targets, Bispecifics Are Poised for Growth
Bispecific antibodies currently in clinical trials for solid tumors have a wide variety of targets.
AstraZeneca has two lead bispecific candidates, targeting PD-1 (Keytruda’s target) plus either CTLA-4 or TIGIT. Volrustomig is a PD-1/CTLA-4 bispecific the company is studying in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Verma explained that the antibody only binds to CTLA-4, a protein found on T cells, in the presence of PD-1 for a coordinated mechanism of action. In the past, magnitude of benefit was limited because CTLA-4 inhibitors were not as combinable with chemotherapy, he said.
Recent data presented at the 2024 World Conference on Lung Cancer (WCLC) showed volrustomig plus chemo to be effective even in patients with PD-L-1 expression less than 1%, a population where traditionally, immune therapy has not been effective. Patients with non-squamous disease saw a response rate of 43%, while 50% of those with squamous disease achieved a response. Verma said this activity profile was much better than what would be seen with chemo alone. A Phase III study is currently underway.
AstraZeneca is also developing rilvegostomig, a PD-1/TIGIT bispecific, which elicited a durable response with favorable tolerability in patients with metastatic NSCLC in a Phase I/II trial. In the group of patients with a PD-L-1 tumor proportion score of 50% or higher, treatment at the 750 mg dose produced an overall response rate of 61.8%.
A key factor for the value of bispecifics comes from their combinability with other cancer therapies, Verma said. To this end, AstraZeneca is also testing rilvegostomig in combination with its approved antibody-drug conjugate (ADC) Enhertu in a Phase III study as a first-line treatment for advanced or metastatic HER2-expressing biliary tract cancer. The two together could really pack a punch, Verma said, with the bispecific engaging and enhancing the immune response while the ADC attacks and kills the cancer cells. The company’s goal is to “beat out the current first generation of PD-1, PD-L-1 [therapies],” but also “improve outcomes for patients and establish [its bispecifics] as the new standard of care.”
Meanwhile, Summit’s ivonescimab is targeting PD-1 and VEGF. At the WCLC, the biotech presented late-phase data showing that ivonescimab outperformed Keytruda as a first-line treatment option in patients with advanced NSCLC. In the Phase III HARMONi-2 trial, treatment with the candidate cut the risk of disease progression or death by nearly 50% compared to Keytruda. While promising, analysts noted that the trial was run entirely in China and said Summit would likely require U.S. data for an FDA approval. A follow-up Phase III in a more diverse population is already planned.
BioNTech is also in the game, developing acasunlimab, an investigational bispecific targeting PD-L-1 and 4-1BB. The candidate uses Genmab’s proprietary DuoBody technology and BioNTech’s antibodies. 4-1BB has emerged as a crucial receptor on both cytotoxic and helper T cells, but clinical development has been historically hindered by toxic adverse events. Simultaneous binding to the secondary site—in acasunlimab’s case, PD-L-1—helps to overcome off-target effects as the drug only activates when present at both binding sites.
Amgen and Johnson & Johnson also have a considerable footprint in this space, with both companies securing approvals this year.
The global market for bispecific antibodies was $8.65 billion in 2023 and could balloon to around $485 billion in the next 10 years, according to Precedence Research. The market potential is huge, Verma said, as is the breadth of patients who could benefit.
With the level of interest in this space, Schoenfeld said one thing is certain: “This therapeutic modality has definitely arrived.”
