%0 Journal Article
%A Fischer, Claudia
%A Chen, Shih-Shih
%A Nimmerfroh, Johanna
%A Eugster, Anne
%A Stücheli, Simon
%A Schultheiß, Christoph
%A Widmer, Corinne
%A Heim, Dominik
%A Kasenda, Benjamin
%A Passweg, Jakob
%A Kobold, Sebastian
%A Egli, Lukas
%A Coianiz, Nicolò
%A Chijioke, Obinna
%A Chiorazzi, Nicholas
%A Follo, Marie
%A Läubli, Heinz
%A Peipp, Matthias
%A Binder, Mascha
%T IGLV3-21R110-directed bispecific antibodies activate T cells and promote killing in a high-risk subset of chronic lymphocytic leukemia.
%J Haematologica
%V nn
%@ 0390-6078
%C Pavia
%I Ferrata Storti Foundation
%M DKFZ-2025-01891
%P nn
%D 2025
%Z epub
%X We previously used a disease-specific B cell receptor (BCR) point mutation (IGLV3-21R110) for selective targeting of a high-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. Since CLL is a disease of the elderly and a significant fraction of patients is not able to physically tolerate CAR T cell treatment, we explored bispecific antibodies as an alternative for precision targeting of this tumor mutation. Heterodimeric IgG1-based antibodies consisting of a fragment crystallizable region (Fc) attached to both an anti-IGLV3-21R110 Fab and an anti-CD3 (UCHT1) single chain variable fragment (R110-bsAb) selectively killed cell lines engineered to express high levels of the neoepitope as well as primary CLL cells using healthy donor and CLL patient-derived T cells as effectors. R110-bsAb spared polyclonal human B cells (as opposed to CD19-targeting Blinatumomab) as well as CD34+ human stem cells. Yet, R110- bsAb induced lower T cell activation than Blinatumomab with primary CLL cells likely due to lower expression of target antigen. In vivo, R110-bsAb specifically killed IGLV3-21R110-expressing cell lines and CLL cells while sparing peripheral blood mononuclear cells. These findings highlight bispecific antibodies as a potential off-the-shelf immunotherapy for high-risk CLL patients, offering selective targeting while preserving healthy B cells.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40931870
%R DOI:10.3324/haematol.2025.287697
%U https://inrepo02.dkfz.de/record/304502