Abstract
Activation of host immune mechanisms using bispecific antibodies is one of a few alternative strategies to address the limitations of the conventional monoclonal antibodies and to improve the efficacy of the targeted cancer therapy. Two single‐chain fragment variable (scFv)-based bispecific antibody formats have been intensively studied preclinically and in clinical trials: tandem scFv molecules [or (scFv)2] and diabodies. Both are small in size and are able to bind the effector and target cells only monovalently. To circumvent the drawbacks of both formats, we have designed a single-chain molecule that is composed solely of the variable (VH and VL) domains from two different specificities and has a modular structure, where a diabody module plays a role of oligomerization motif due to interchain pairing of the cognate VH and VL domains. The resulting bispecific scFvA–diabodyB–scFvA tandem molecules (where A and B are different specificities), which we called ‘flexibodies’, possess structural flexibility, bind bivalently to both effector and target cell, and are able to cross-link spatially distinct antigens. Here, we report effective killing of malignant primary B cells from patients with B-cell chronic lymphocytic leukemia mediated by bispecific CD19×CD3 flexibodies at very low effector-to-target cell ratios. Use of tetravalent flexibodies caused almost quantitative elimination of leukemia cells from the blood samples of B‐cell chronic lymphocytic leukemia patients, while the structurally similar but bivalent (scFv)2 molecules showed no antitumor activity. These data demonstrate that the novel oligovalent flexibody format might be a promising tool for treatment of human malignancies.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.