TY  - JOUR
AU  - Fischer, Claudia
AU  - Chen, Shih-Shih
AU  - Nimmerfroh, Johanna
AU  - Eugster, Anne
AU  - Stücheli, Simon
AU  - Schultheiß, Christoph
AU  - Widmer, Corinne
AU  - Heim, Dominik
AU  - Kasenda, Benjamin
AU  - Passweg, Jakob
AU  - Kobold, Sebastian
AU  - Egli, Lukas
AU  - Coianiz, Nicolò
AU  - Chijioke, Obinna
AU  - Chiorazzi, Nicholas
AU  - Follo, Marie
AU  - Läubli, Heinz
AU  - Peipp, Matthias
AU  - Binder, Mascha
TI  - IGLV3-21R110-directed bispecific antibodies activate T cells and promote killing in a high-risk subset of chronic lymphocytic leukemia.
JO  - Haematologica
VL  - nn
SN  - 0390-6078
CY  - Pavia
PB  - Ferrata Storti Foundation
M1  - DKFZ-2025-01891
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40931870
DO  - DOI:DOI:10.3324/haematol.2025.287697
UR  - https://inrepo02.dkfz.de/record/304502
ER  -