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Fischer, C.* ; Chen, S.S.* ; Nimmerfroh, J.* ; Eugster, A.* ; Stücheli, S.* ; Schultheiß, C.* ; Widmer, C.* ; Heim, D.* ; Kasenda, B.* ; Passweg, J.* ; Kobold, S. ; Egli, L.* ; Coianiz, N.* ; Chijioke, O.* ; Chiorazzi, N.* ; Follo, M.* ; Läubli, H.* ; Peipp, M.* ; Binder, M.*

IGLV3-21R110-directed bispecific antibodies activate T cells and promote killing in a high-risk subset of chronic lymphocytic leukemia.

Haematologica, DOI: 10.3324/haematol.2025.287697 (2025)
Postprint DOI PMC
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0390-6078
e-ISSN 1592-8721
Journal Haematologica - The Hematology Journal
Publisher Ferrata Storti Foundation
Reviewing status Peer reviewed
Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)