Modulating the immune system using monoclonal antibodies (mAbs) is a promising approach in cancer immunotherapy. Currently, clinically approved immunotherapy agents consist of antagonistic mAbs against CTLA-4 and PD-L1, immune checkpoint inhibitors that work by disabling the brakes on the immune system. Another approach in active clinical development is directly boosting the immune system through co-stimulatory receptors of the tumor necrosis factor receptor superfamily (TNFRS). The first generation of agonistic mAbs activating 4-1BB (CD137), a TNFRS co-stimulatory molecule, were unsuccessful due to adverse effects in patients.
In a recent Nature Communications article, Compte et al. use a protein engineering approach to design next-generation 4-1BB agonists. They created trimeric recombinant 4-1BB agonistic mAbs by replacing the toxicity-mediating Fc region with the homotrimerization region of murine collagen XVIII, thereby mimicking the physiological trimeric 4-1BB-Ligand. The mAb was further made bispecific by including tumor-antigen targeting domains. Various biophysical and cellular analyses were performed to screen and characterize the mAbs. Mix-n-Stain™ CF®488A and CF®647 kits were used to label the trimeric mAbs and murine 4-1BB to monitor receptor dynamics in transfected cells and determine in vivo tumor localization in mice. The resulting bispecific trimerbody showed high avidity, potent co-stimulatory activity, high tumor specificity, and similar anti-tumor activity without the toxicity associated with the conventional 4-1BB mAb. The study demonstrates an alternate approach for designing safe, effective co-stimulatory antibody-based cancer immunotherapeutics.
Compte M, Harwood SL, Muñoz IG, Navarro R, Zonca M, Perez-Chacon G, Erce-Llamazares A, Merino N, Tapia-Galisteo A, Cuesta AM, Mikkelsen K, Caleiras E, Nuñez-Prado N, Aznar MA, Lykkemark S, Martínez-Torrecuadrada J, Melero I, Blanco FJ, Bernardino de la Serna J, Zapata JM, Sanz L, Alvarez-Vallina L. A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity. Nat Commun. 2018 Nov 15;9(1):4809. doi:10.1038/s41467-018-07195-w.