From bispecific to multispecific antibodies: a highly promising field

Bispecific antibody therapies provide a novel way of creating differentiated drug activity, such as synthetic immunity, that is more than the sum of its parts. The field really began to gain ground around 2009 with the approval of the first bispecific antibody catumaxomab, a T-cell engager bispecific targeting EpCAM, followed by the approval of the bispecific T-cell engager (BiTE) molecule blinatumomab, a CD19xCD3 T-cell engager, in 2014. While these types of molecules have shown some success in different types of cancer, limits to their capability and applicability have become apparent. One challenge is the lack of effective agents for solid tumours. Worldwide, of the 11 immune cell engagers with regulatory approval, only three are for solid tumours. This may be due in part to the tumour’s physical barrier, reduced infiltration, and the health status of the immune cells. The efficacy of bispecifics is also compromised by antigen escape-mediated resistance, issues around T-cell dysfunction and immunosuppression, and by toxicity, such as the infectious complications and hypogammaglobulinaemia seen with B- and plasma-cell targeting bispecifics.

Trispecific antibodies were developed as a way of overcoming some of these hurdles. Dual tumour-antigen targeting T-cell engagers, combining a tumour-antigen binding antibody with an effector T-cell (CD3) arm and a second tumour-associated antigen binding arm (J Pharmacol Exp Ther. 2025;392:103704; MAbs. 2026;18:2613548), help to reduce resistance due to antigen escape, thereby leading to longer, more durable responses. Targeting multiple tumour antigens also tackles the problem posed by tumour cell heterogeneity. An example of this type of agent, BCMAxGPRC5DxCD3, is showing promising activity in relapsed/refractory multiple myeloma (Blood 2025;146(Suppl1):4042).

Co-stimulatory trispecific T-cell engagers, which combine a tumour-antigen binding antibody with a CD3 arm and an additional arm targeting a costimulatory receptor – frequently CD28 – enhance the depth and duration of the T-cell response in the presence of tumour binding (J Immunother Cancer. 2025;13:e010140; Cancer Res. 2025:85(8_Suppl_1):7318). This is still an emerging class of agents and potential challenges are evidenced by phase I trial data with the CD38xCD3xCD28 trispecific SAR442257 in multiple myeloma and non-Hodgkin lymphoma, which showed only modest efficacy but also revealed toxicity concerns, particularly infectious complications (Blood 2024;144(Suppl 1):1992).

Multi-specific agent development builds on the lessons learned from bispecifics and trispecifics. In this regard, it is really interesting to see in vitro and in vivo findings presented at the ESMO Targeted Anticancer Therapies Congress 2026 (Paris, 16–18 March) for two novel tetraspecific T-cell engagers (MDX2001 [CD3xCD28xcMETxTrop2] and MDX2003 [CD3xCD28xCD19xCD20]), an approach that essentially combines dual antigen targeting with costimulation (Abstract 1MO). The results demonstrated the ability of these agents to overcome tumour heterogeneity and enhance T-cell activation, proliferation and survival relative to CD3-only targeting. MDX2003 was also able to overcome single-antigen escape.

Although multispecifics offer huge clinical potential, their development faces a number of potential hurdles. One is the complex engineering requirements to obtain the desired biology, particularly when considering the addition of a new function, such as a costimulant. There is a fine line between positive and negative effects when engaging two different targets on an immune cell with the same targeted agent. And in terms of clinical trials, we are entering a new territory that requires clear definition of the targets to be assessed and the biomarkers that can be used to assess response for this new class of agents. Because of this, comprehensive phase I trial protocols will be critical. Finally, as the complexity of molecules increases, so does the importance of developability and impacts on chemistry, manufacturing and controls.

This is an exciting time not just for novel multitargeted agents but also for improved bi- and trispecifics. For example, encouraging phase I trial efficacy has been seen with bispecifics in many solid tumour settings, including with the CD3/KLK2-targeting bispecific pasritamig (J Clin Oncol. 2025;43:2515–2526). Combination therapy is another promising avenue, as shown by results with the BiTE tarlatamab plus a PD-L1 checkpoint inhibitor in small cell lung cancer after first-line chemoimmunotherapy (Lancet Oncol. 2025;26:1300–1311): a phase III trial is ongoing (NCT06211036). Then there is the potential for different approaches, such as conditionally active molecules, like the masked bispecifics, which become active only systemically or in the tumour microenvironment, thereby limiting toxicity (Cancer Res. 2022;82:4288–4298). Additionally, the emerging trispecific clinical data are very promising showing that overall, the future for multispecific therapies is definitely bright.