Multispecific antibodies have appeared as a revolutionary family of targeted drugs, providing the potential for the simultaneous binding of two or more antigens or epitopes. This feature is revolutionizing the therapeutic approach to multifactorial diseases like cancer, autoimmune diseases, and infectious infections. By moving beyond the conventional monoclonal and even bispecific antibodies, multispecific formats like trispecific and tetraspecific antibodies are allowing more targeted, efficient, and sustained therapeutic approaches. According to Neeraj Chawla, Founder & Research Head at Kuick Research, the commercial success of bispecific antibodies in last decade with cumulative sales of more than USD 35 Billion and ongoing clinical trials of more than 700 multispecific antibodies (bispecific, trispecific and tetraspecific ) has further strengthen the fact that there exist multibillion dollar opportunity of multispecific antibodies which still remain unexplored.
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The major advantage of multispecific antibodies is that they can target several disease-related targets simultaneously. This multi-target approach increases therapeutic specificity, facilitates the engagement of the immune system more efficiently, and diminishes the risk of resistance, a general drawback of monospecific treatment. In cancer, in which tumor heterogeneity and immune escape present formidable challenges, multispecific antibodies are proving especially useful.
For instance, CMG1A46 is a trispecific antibody that was first developed by Chimagen and was later acquired by GSK in October 2024 to continue developing for B cell–mediated autoimmune diseases. CMG1A46 acts on CD3 present on T cells and CD19 and CD20 present on B cells to allow specific T-cell redirection to destroy B cells with either or both markers. Although first developed for application in hematological malignancies, its mechanism has been harnessed to eliminate pathogenic B cells in autoimmune diseases. Potent cytotoxicity with lower off-target activity has been shown through preclinical studies, with possible application as a targeted immunotherapy in a wide range of disease indications.
Trispecific antibodies against the Eph receptor family, targeted to EphA2, EphA4, and EphB4, is another new strategy. These receptors play roles in tumor growth and angiogenesis. A recombinant antibody targeting all of these receptors at the same time has been able to induce internalization and degradation of the receptors and, as a result, inhibit the growth of tumors in preclinical models. This pathway-disrupting, targeted approach illustrates the means by which multispecific antibodies can target multiple oncogenic signaling pathways simultaneously.
Checkpoint inhibition is also being transformed by multispecific platforms. Conventional immune checkpoint inhibitors tend to be administered as combination regimens with elevated toxicity and cost. Conversely, multispecific antibodies targeting the simultaneous blockade of PD-1/PD-L1 and CTLA-4, or emerging checkpoints such as LAG-3 and TIM-3, provide a single-agent regimen with greater immune activation. These tools are reprogramming the immune response more broadly, meeting the complexity of tumor immune evasion mechanisms, and enhancing clinical efficacy for various solid tumor indications.
In the context of innate immunity, GTB-3650 is a second-generation trispecific killer engager (TriKE) that is intended to augment natural killer (NK) cell-mediated killing. It engages CD33 on AML cells and CD16 on NK cells, with the addition of an IL-15 moiety to augment NK cell activation and expansion. This targeted treatment is a promising option for patients with acute myeloid leukemia, a cancer frequently refractory to traditional treatments.
Following in this trend, in the future, tetraspecific antibodies with the ability to bind four unique targets are expected to gain more prominence. These next-generation constructs have the potential to affect multiple disease processes at once, for example, tumor formation, immune suppression, and metastasis, thus providing strongly personalized therapeutic responses. While mostly still in initial stages of development, tetraspecifics are the forefront of antibody engineering.
Overall, multispecific antibodies are revolutionizing targeted treatment. By addressing more than one target with one agent, they provide improved efficacy, decreased resistance, and improved disease management. As science continues to evolve, these compound biologics will become key agents in precision medicine for a wide range of diseases.
