Journal Article

DKFZ-2025-01891

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png IGLV3-21R110-directed bispecific antibodies activate T cells and promote killing in a high-risk subset of chronic lymphocytic leukemia.

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

2025
Ferrata Storti Foundation Pavia

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Please use a persistent id in citations: doi:DOI:10.3324/haematol.2025.287697   doi:DOI:10.3324/haematol.2025.287697

Abstract: 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.

Note: epub

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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