Session

21
Oral presentations Experimental hematology / oncology
Nov. 20, 2024, 1:45 p.m. - 3:15 p.m., Shanghai 1-2

Abstract

6
IGLV3-21-G110R-directed bispecific antibodies activate T cells and induce killing in a high-risk subset of chronic lymphocytic leukaemia
C. Fischer1, S. Stücheli1, C. Schultheiss1, C. Widmer1, D. Heim1, B. Kasenda1, J. Passweg1, S. Kobold2, L. Egli3, N. Coianiz3, O. Chijioke3, M. Peipp4, M. Binder1, Presenter: C. Fischer1 (1Basel, 2Munich, 3Zurich, 4Kiel)

Objective
The development of chimeric antigen receptor (CAR) T cells or bispecific antibodies represents significant progress towards more precise cellular therapies for cancer. Notable examples include anti-CD19 CAR T cells or the anti-CD3xCD19 T cell engager Blinatumomab. However, both therapies can lead to the complete eradication of the patient`s B cells. We previously provided proof of principle that an aggressive and treatment requiring subset of chronic lymphocytic leukaemia (CLL) carrying the highly oncogenic G110R mutation on its stereotyped immunoglobulin light chain variable 3-21 (IGLV3-21-G110R) can be treated with G110R-point mutation-specific CAR T cells. Here, we introduce an alternative strategy for targeting this CLL subset utilizing the bispecific antibody R110-bsAb.
Methods
We designed the heterodimeric, bispecific antibody targeting CD3 on T cells with a single-chain variable fragment (scFv) on the one arm and an anti-IGLV3-21-G110R antigen-binding fragment (Fab) targeting the CLL-specific IGLV3-21-G110R neoepitope on the other arm. For in vitro experiments, we engineered cell lines to express the B cell receptor (BCR) with the IGLV3-21 wild-type (G110) or mutated (R110) variant and performed co-culture assays with healthy donor or CLL-derived T cells. We further tested primary CLL, healthy B and hematopoietic stem cells (HSC) to assess the specificity of target cell killing and activation of T cells.
Results
In vitro experiments demonstrated the efficient and target-specific cell lysis of the engineered cell lines while sparing cells carrying a random BCR light chain or the IGLV3-21 wild-type light chain. Furthermore, T cell activation only occurred in the presence of the target mutation, and the anti-IGLV3-21-G110R antibody moiety alone did not induce apoptosis or activation. Cytolysis of primary CLL and T cell activation were lower as compared to cell lines. Polyclonal human B cells or HSCs are unaffected by the R110-bsAb. T cells derived from CLL patients were also activated and effectively lysed target cells in the presence of the R110-bsAb, while R110-negative cell lines remained unaffected.
Conclusion
Together, these data advocate for the continued exploration of bispecific antibodies for an off-the-shelf, tolerable immunotherapy that only targets relevant, high-risk mutations in a subset of CLL.
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