Catumaxomab

iStock/ 111chemodan111 As companies roll out data showing the power and improved safety pro 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 pro 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.”

“Bispecific Antibodies Sales Surpassed USD 8 Billion In 2023 With More Than 50% YOY Growth” Bispecific antibodies represent a cutting edge class of therapeutic agents at the forefront of revolutionizing modern medicine. These molecules, engineered to bind simultaneously to two different targets, offer a unique and potent approach to treating a variety of diseases, particularly cancer. With their ability to harness the body's immune system to precisely target tumor cells while sparing healthy tissue, bispecific antibodies have garnered significant attention in both clinical and commercial markets across the globe. Clinically, bispecific antibodies clench immense promise as a cornerstone of precision medicine, offering targeted therapy tailored to individual patients' molecular pro By engaging immune effector cells, such as T cells or natural killer (NK) cells, bispecific antibodies orchestrate precise and potent immune responses against cancer cells, leading to tumor regression and improved patient outcomes. The versatility of bispecific antibodies allows for the development of therapies targeting various tumor antigens and immune cell populations, spanning a broad range of cancers and other ailments. Download Research: Besides that, the commercial market for bispecific antibodies is experiencing rapid growth, driven by the increasing demand for innovative and effective therapies across diverse therapeutic areas. The approval and commercial success of several bispecific antibodies, such as blinatumomab for acute lymphoblastic leukemia (ALL) and catumaxomab for malignant ascites, have validated the therapeutic potential of this class of molecules and spurred further investment and development. Pharmaceutical companies, biotechnology firms, and academic institutions are actively pursuing bispecific antibody programs, capitalizing on advancements in antibody engineering technology and strategic collaborations to accelerate the translation of promising candidates into clinical market. Several key factors driving the clinical and commercial success of bispecific antibodies include rise in cancer incidences, augmenting research and development, involvements of various stakeholders from the pharma and biotech company along with fostering research collaborations and investments in the realm. For instance, in December 2023, a research collaboration and license agreement are signed by Elpiscience and Astellas for the novel bispecific macrophage engager, ES019, and other programs. For these two programs, both the companies will work together to conduct early-stage research. In addition to cancer malignancies, other disorders like autoimmune diseases, infectious diseases, and neurological disorders are also being researched in the sphere. Their adaptable mode of action and capacity to interact with various targets render them appealing options for tackling unfulfilled medical requirements in various therapeutic domains. For instance, in a study conducted by researchers at The University of Texas MD Anderson Cancer Center, in 2023, developed fully human bispecific antibodies that bind to two different epitopes of the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and neutralize a wide range of variants including the Omicron variant. One of the key prime movers which aid to expand the market of bispecific antibodies is the bestow from regulatory agencies and augmenting approval to novel and innovative bispecific antibodies. For instance, in August 2023, European Commission (EC) has approved TALVEY (talquetamab) for use as a monotherapy in treating adult patients with relapsed and refractory multiple myeloma (RRMM). Talquetamab is a bispecific antibody that engages T cells specifically by binding to CD3, which is present on the surface of T cells, and G protein-coupled receptor class C group 5 member D (GPRC5D), a novel target that is expressed on the surface of hard keratinized tissues and multiple myeloma cells. Looking ahead, the commercial market for bispecific antibodies holds immense potential for growth and expansion. Continued research, clinical development, and regulatory approvals will be instrumental in unlocking the full therapeutic potential of bispecific antibodies and addressing unmet medical needs across diverse patient populations. With their transformative impact on patient care and the potential to reshape the treatment landscape, bispecific antibodies are poised to play a pivotal role in advancing the future of medicine and improving outcomes for patients worldwide.