Week 1, August 2025: Renewing Hope with Trispecific Antibodies

Trispecific antibodies are engineered proteins that can bind to three different targets at the same time. This design allows for more complex interactions than monospecific or bispecific antibodies and can be used to improve targeting, immune cell engagement, or signaling modulation. Here, we examine trispecific T cell engagers (TCEs), applications in different types of cancer, examples of newly developed trispecific antibodies, and recent commercial agreements. 

A review from researchers at the University of Oxford describes how the development of trispecific TCEs reflects a stepwise effort to overcome limitations seen with earlier immunotherapies. Early bispecific formats, such as 1+1 designs, were limited by issues like poor tumour selectivity and incomplete T cell activation. Advances to 2+1 formats improved avidity and tumour selectivity by incorporating two tumour-binding arms. More recently, 1+1+1 trispecific designs have been introduced, allowing for the simultaneous engagement of three different targets. In trispecific TCEs, one arm typically binds CD3 on T cells, while the other two either target two distinct tumour antigens or combine a tumour antigen with a T cell co-stimulatory receptor. These formats aim to address key therapeutic challenges, including tumour heterogeneity and insufficient T cell activation. Trispecific TCEs generally fall into two categories: dual-tumour targeting and co-stimulatory. The former targets two antigens on tumour cells to reduce immune escape, while the latter includes a co-stimulatory signal to enhance T cell function, particularly in immunosuppressive tumour environments. 

Examples of trispecific TCEs can be seen in recent studies. For instance, a study by the University of Minnesota developed a modular platform using a chemically self-assembled nanoring (CSAN) system for trispecific TCEs capable of targeting multiple tumour antigens simultaneously while maintaining T cell-dependent cytotoxicity. This approach showed that combining antigen specificities within a single construct can enhance tumour recognition and killing across variable antigen expression profiles, a key issue in solid cancers like breast cancer. Meanwhile, researchers from the University of Stuttgart developed a trispecific TCE using an eFab-eIg format targeting HER2, HER3, and CD3, which was effective at redirecting T cells to tumour cells expressing either or both HER family antigens. The findings from both studies underscore that modular trispecific designs can be engineered to retain functional binding to all intended targets and improve T cell engagement, supporting their potential to overcome antigen loss and intratumoural heterogeneity. 

Trispecific antibodies are now being investigated across a range of cancers. In hematologic malignancies such as acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma, trispecifics improve antigen coverage and T cell activation. For example, ISB 2001, a CD38×BCMA×CD3 TCE, has shown strong clinical activity in relapsed/refractory multiple myeloma, including in patients previously treated with CAR T-cell or anti-BCMA therapies. Its design enables high-affinity tumour binding and reduced CD3-mediated toxicity, resulting in durable responses and manageable safety. In solid tumours, trispecifics are also gaining traction. A CDLN-18.2×CD3×CD28 TCE showed preclinical efficacy in gastric cancer by enhancing T cell co-stimulation and tumour cell killing. In head and neck squamous cell carcinoma, a trispecific killer engager (TriKE) targeting B7-H3 and CD16, with an IL-15 domain for NK cell activation, demonstrated improved cytotoxicity even in hypoxic conditions typical of this tumour type. These examples underscore how trispecific antibodies are a broadly applicable and increasingly promising class of immunotherapy agents. 

The growing commercial interest in trispecific antibodies is reflected in recent high-value deals, particularly in multiple myeloma. AbbVie’s $700 million upfront payment to Ichnos Glenmark Innovation (IGI) for rights to ISB 2001, a CD38×BCMA×CD3 trispecific TCE, signals strong confidence in the therapeutic potential of this format. The agreement, which includes up to $1.225 billion in additional milestones, positions AbbVie to compete directly with existing BCMA×CD3 bispecifics from Johnson & Johnson, Pfizer, and Regeneron. By including CD38, ISB 2001 may overcome resistance in patients with low BCMA expression or prior exposure to BCMA-targeted therapies. Phase 1 data showed a 79% response rate and nearly 30% complete responses, with no dose-limiting toxicities and manageable cytokine release syndrome. This follows another AbbVie investment earlier in 2025 for SIM0500, a BCMA×GPRC5D×CD3 trispecific from Simcere Zaiming.