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Tropomyosin kinase B (TrkB) plays an important role in survival, differentiation, and proliferation of neural cells. It belongs to the family of receptor tyrosine kinases and its specific ligands are NT-4/5 and BDNF. The (over)expression of TrkB and (over)activation of the BDNF/TrkB signaling pathway is implicated in various solid malignancies and associated with poor prognosis due to the role of TrkB in suppressing anoikis and promoting epithelial-mesenchymal transition. Here we present the development and characterization of novel T cell engagers targeting TrkB. A panel of 41 sequence unique antibodies were selected from human phage display libraries and B cells of TrkB-ECD immunized chicken. Following recombinant expression, the panel of antibodies was analyzed for off-rate, binding reactivity to plate-immobilized and cell-expressed TrkB, cross-reactivity to other tropomyosin kinase family members, and competition with BDNF. Based on their characteristics, two targeting arms were prioritized for the generation of T cell engagers using a standard bispecific knob-into-hole approach. Apart from a commercial CD3 targeting arm, three proprietary CD3 targeting arms were also analyzed. After successful production of the bispecifics , the molecules were validated to bind to plate-immobilized TrkB and CD3 separately and cell-associated TrkB and CD3 simultaneously. In addition, our TrkB T cell engagers were able to induce varying levels of T cell activation in vitro. Our data suggests that these TrkB/CD3 bispecific molecules could be interesting candidates for further development into immuno-oncology therapeutics. Citation Format: Jetta Bijlsma, Srinidhi Desikan, Timothy Miller, Allie Thom, Jennifer Bath, Ilse Roodink. Bispecific T cell engagers targeting TrkB [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1890. |
