An innovative antibody fusion protein targeting PD-L1, VEGF and TGF- β with enhanced antitumor efficacies

Int Immunopharmacol. 2024 Feb 19;130:111698. doi: 10.1016/j.intimp.2024.111698. Online ahead of print.ABSTRACTImmunosuppressive pathways in the tumor microenvironment (TME) are inextricably linked to tumor progression. Mono-therapeutics of immune checkpoint inhibitors (ICIs, e.g. antibodies against programmed cell death protein-1/programmed cell death ligand-1, PD-1/PD-L1) is prone to immune escape while combination therapeutics tends to cause high toxicity and side effects. Therefore, using multi-functional molecules to target multiple pathways simultaneously is becoming a new strategy for cancer therapies. Here, we developed a trifunctional fusion protein, DR30206, composed of Bevacizumab (an antibody against VEGF), and a variable domain of heavy chain of heavy chain antibody (VHH) against PD-L1 and the extracellular domain (ECD) protein of TGF-β receptor II (TGF-β RII), which are fused to the N- and C-terminus of Bevacizumab, respectively. The original intention of DR30206 design was to enhance the immune responses pairs by targeting PD-L1 while inhibiting VEGF and TGF-β in the TME. Our data demonstrated that DR30206 exhibits high antigen-binding affinities and efficient blocking capabilities, the principal drivers of efficacy in antibody therapy. Furthermore, the capability of eliciting antibody-dependent cellular cytotoxicity (ADCC) and mixed lymphocyte reaction (MLR) provides a greater possibility to enhance the immune response. Finally, in vivo experiments showed th...
Source: International Immunopharmacology - Category: Allergy & Immunology Authors: Source Type: research