Data for BBA General - bbagen.2025.130867

Figshare · 2026-04-13

Data to accompany BBA General - bbagen.2025.130867

Data for BBA General - bbagen.2025.130867

Figshare · 2026-04-13

Data to accompany BBA General - bbagen.2025.130867

Two-component T-cell immunotherapy enables antigen pre-targeting to reduce cytokine release without forfeiting efficacy

Nanomedicine Nanotechnology Biology and Medicine · 2025-04-30 · 2 citations

Contemporary T-cell immunotherapies, despite impressive targeting precision, are hindered by aberrant cytokine release and restrictive targeting stoichiometry. We introduce a two-component T-cell immunotherapy targeting B-cell malignancies: Multi-Antigen T-Cell Hybridizers (MATCH). This split antibody technology differs from current therapies by separating cancer cell-targeting components from T cell-engaging components. We demonstrate that this two-component structure facilitates tunable T-cell activation. αCD19 and αCD20 MATCH, administered in two steps, are both compared to the clinical standard bispecific antibody, blinatumomab. In vitro two-dimensional dose analysis and cytokine release data indicate MATCH improves cancer clearance with reduced cytokine release. Cytolytic mechanisms of action are evaluated. αCD20 MATCH anti-cancer efficacy is assayed using a human lymphoma murine model. Decreasing T-cell engager dose 10-fold yields comparable efficacy to non-reduced doses. Ultimately, this split-antibody paradigm may enhance antigen targeting while reducing cytokine release, with such safety and efficacy advantages augmented by the future possibility of multi-antigen targeting with MATCH.

Modular Synthesis of Anti-HER2 Dual-Drug Antibody-Drug Conjugates Demonstrating Improved Toxicity

Bioconjugate Chemistry · 2025-01-22 · 6 citations

Antibodies have gained clinical success in the last two decades for the targeted delivery of highly toxic small molecule chemotherapeutics. Yet antibody-drug conjugates (ADCs) often fail in the clinic due to the development of resistance. The delivery of two mechanistically distinct small molecule drugs on one antibody is of increasing interest to overcome these challenges with single-drug ADCs. We have developed a modular synthetic strategy for the construction of a library of 19 dual-drug ADCs where drugs are conjugated through unnatural cyclopentadiene-containing amino acids and native cysteine residues on an anti-HER2 trastuzumab scaffold. Importantly, this strategy utilizes the same functional group on the linker-drug construct; this allows for the facile addition of drugs at either conjugation site and enables the evaluation of different drug-to-antibody ratios and combinations of drug pairs. We tested the library on high- and mid-HER2 expressing cell lines and observed increased toxicity in several dual-drug ADCs compared with single-drug constructs. The strategy developed herein provides a method for the facile synthesis, characterization, and evaluation of dual-payload ADCs. Simultaneous delivery of combinations of drugs with distinct mechanisms of action is critical for the next generation of targeted drug delivery.

Selection and evaluation of new sites for splitting beta-lactamase to modulate auto-complementation enzyme activity

Biochimica et Biophysica Acta (BBA) - General Subjects · 2025-10-25

Emerging Voices in Drug Delivery – Harnessing and Modulating Complex Biological Systems (Issue 2)

Advanced Drug Delivery Reviews · 2024-03-21 · 1 citations

Emerging Voices in Drug Delivery – Breaking Barriers (Issue 1)

Advanced Drug Delivery Reviews · 2024-03-05

Bioluminescence assay of lysine deacylase sirtuin activity

Cell chemical biology · 2024-11-01 · 1 citations

Surface-Available HER2 Levels Alone Are Not Indicative of Cell Response to HER2-Targeted Antibody–Drug Conjugate Therapies

Pharmaceutics · 2024-06-02 · 4 citations

HER2-targeting therapies have advanced breast cancer treatment over the past decade. Clinically, eligibility for HER2 therapies is determined by assessing HER2 levels on tumor cell surfaces through immunohistochemistry or by gene regulation through fluorescence in situ hybridization. HER2 therapies are not always effective in patients with elevated levels of HER2, questioning whether the amount of HER2 is sufficiently predictive of patient outcomes. Additionally, the HER2-targeting antibody–drug conjugate (ADC) Enhertu® was recently approved for metastasized HER2-low cancers, confirming the benefits of HER2 treatment for patients with low HER2 levels. To evaluate the correlation between HER2 levels and treatment efficacy, we quantified HER2 on eight cell lines using flow cytometry while simultaneously determining the toxicity of two HER2-targeting ADCs. Both HER2-high cell lines and HER2-low cell lines had significant toxicity responses to ADCs. We quantified HER2 internalization and found no correlation between HER2 levels and the percentage of internalization. We found a useful metric suggesting that a minimum number of HER2 receptors trafficked to lysosomes is sufficient to provide effective treatment. Our results indicate that the current standards of determining eligibility for HER2 therapy could limit patients’ access to effective treatment. In conclusion, HER2 levels are not wholly adequate to determine the response to ADC treatment.

Supplementary Table 1 from SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia

2023-04-04

<p>Patient sample information.</p>