mAbs · Available online 6 Feb 2026 · In press · DOI 10.1080/19420862.2026.2622746
Driven by the substantial limitations of first generation 4–1BB agonists urelumab and utomilumab, the field has shifted toward engineering next-generation molecules with improved therapeutic windows. This review provides a comprehensive analysis of this evolution, detailing how key molecular design strategies are used to restrict 4–1BB activation to the tumor microenvironment. We summarize available clinical data, highlighting that 4–1BB bispecific antibodies exhibit superior antitumor efficacy and more favorable safety profiles compared with their monospecific predecessors. Furthermore, we discuss strong rationale for combination strategies, emphasizing how 4–1BB signaling provides the crucial costimulatory signal necessary to sustain durable anti-tumor responses. In summary, this review elucidates the scientific basis of antibody engineering aimed at improving safety and tumor-selective activation of 4–1BB agonists and outlines future directions for optimizing their clinical application in cancer immunotherapy.
Abstract from DOAJ. Public domain (CC0 1.0).
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