Identification of New DR5 Agonistic Nanobodies and Generation of Multivalent Nanobody Constructs for Cancer Treatment

International Journal of Molecular Sciences

Sam Massa¹  Ema Romão¹  Serge Muyldermans¹  Khosro Khajeh²  Sadegh Hassania²  Golnaz Sadeghnezhad²  Robert Bernedo-Navarro³ 

[1] Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels 1050, Belgium;Faculty of Biological Sciences, Tarbiat Modares University, Teheran 14115-331, Iran;Laboratory of Environmental and Life Sciences, University of Nova Gorica, Nova Gorica 5000, Slovenia;

关键词: death receptor 5;    nanobody;    trail;    cancer therapy;    apoptosis;   

DOI  :  10.3390/ijms20194818

来源: DOAJ

【 摘 要 】

Current cancer therapeutics suffer from a lack of specificity in targeting tumor cells and cause severe side effects. Therefore, the design of highly specialized drugs comprising antibody derivatives inducing apoptosis in targeted cancer cells is considered to be a promising strategy. Drugs acting on death receptor 5 (DR5) such as DR5 agonist antibodies replacing “TNF-related apoptosis-inducing ligand” (TRAIL) offer feasible opportunities in this direction. Although such agonists provided good antitumor activity in preclinical studies, they were less effective in clinical studies, possibly due to a disturbed Fc interaction with Fc-γ receptors. Thus, multimerized antigen binding fragments without Fc have been proposed to increase their efficacy. We generated nanobodies (Nbs), recombinant variable domains of heavy chain-only antibodies of camelids, against the DR5 ectodomain. Nb24 and Nb28 had an affinity in the nM and sub-nM range, but only Nb28 competes with TRAIL for binding to DR5. Bivalent, trivalent, and tetravalent constructs were generated, as well as an innovative pentameric Nb complex, to provoke avidity effects. In our cellular assays, these trimeric, tetrameric, and pentameric Nbs have a higher apoptotic capacity than monomeric Nbs and seem to mimic the activity of the natural TRAIL ligand on various cancer cells.

【 授权许可】

Unknown