Biology subjects

Gehlert, C. L.

Publications and source records attributed to Gehlert, C. L..

3 recordsLinked to original sources

bioRxiv2026

A Novel Natural Killer Cell Expansion Technology for the Development of Cellular Immunotherapies

Adoptive cell therapy based on Natural Killer (NK) cells holds great promise for the treatment of cancer. For all approaches aiming at utilizing NK cells in immunotherapy, efficient ex vivo expansion technologies for the generation on of cytotoxic NK cells are a prerequisite for clinical translation. In this study, a novel multifunctional fusion protein consisting of a CD20-directed Fab-fragment, an agonistic anti-4-1BB single-chain Fragment variable (scFv), the Sushi domain of the interleukin (IL)-15 receptor and human IL-15 was generated. This molecule triggered strong NK cell expansion when bound to co-cultivated autologous B cells, due to trans-presentation of IL-15 and binding to 4-1BB/CD137. Expansion rates of up to 7,500-fold were achieved and the NK cells showed high cytotoxic capacity against a panel of tumor cell lines representing various tumor entities. Importantly, the activated NK cells did not show cytolytic activity against non-malignant B cells indicating that NK cells amplified by our novel approach were still physiologically regulated. The cytotoxic activity of the expanded NK cells was further enhanced by combination with therapeutic antibodies. Our molecule was additionally able to trigger efficient proliferation of NK cells from cord blood as well as multiple myeloma (MM) and acute myeloid leukemia (AML) patients. In conclusion, our novel platform technology provides ex vivo expansion of NK cells by using a single multifunctional fusion protein and may be well-suited for the development of NK cell-based immunotherapies. Key pointsA novel fusion protein that enables NK cell expansion from different sources including peripheral blood, bone marrow and cord blood

immunology↗

bioRxiv2025

A novel Fc-optimized antibody drug conjugate targeting CD7 for the therapy of T-cell acute lymphoblastic leukemia

While treatment for patients with T-cell acute lymphoblastic leukemia (T-ALL) has improved in the last decades, therapeutic options for patients refractory to standard therapy or with relapsing disease are limited. In particular, no immunotherapy option has been approved in T-ALL yet. Here, a novel dual antibody engineering approach for targeting CD7 was evaluated. The chimeric CD7 antibody chimTH69 was modified by Fc engineering to improve antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In addition, it was conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The resulting Fc-optimized antibody-drug conjugate (ADC), designated chimTH69-DE-vcMMAE, showed a unique set of effector functions in vitro. It triggered ADCC by mononuclear cells at picomolar concentrations, mediated ADCP by macrophages and directly inhibited the growth of a panel of T-ALL cell lines by delivering the cytotoxic compound to induce G2 cell cycle arrest and apoptosis. In addition, due to its specific linker design, chimTH69-DE-vcMMAE demonstrated bystander killing activity against CD7-negative leukemia cells. In mice, CD7-directed therapy with chimTH69-DE-vcMMAE inhibited the growth of subcutaneous CCRF-CEM T-ALL xenografts. Moreover, chimTH69-DE-vcMMAE exerted strong antileukemic effects in a phase II-like patient-derived xenograft preclinical trial in pediatric and adult patients when applied in an experimental overt leukemia setting. ChimTH69-DE-vcMMAE induced minimal residual disease-negativity in one PDX model. These findings indicate that targeting CD7 with the novel Fc-optimized ADC is a potent strategy to trigger anti-leukemia responses and may open a novel therapeutic avenue for T-ALL treatment. Key PointA novel antibody drug conjugate targeting CD7 showed efficient anti-leukemia activity in preclinical models of T-ALL.

cancer biology↗

bioRxiv2023

CD20 expression regulates CD37 levels in B-cell lymphoma: implications for immunotherapies.

Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized with a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate for the first time that CD20 and CD37 form a complex and the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates. Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.

cancer biology↗