Biology subjects

Gerlach, M.

Publications and source records attributed to Gerlach, M..

4 recordsLinked to original sources

bioRxiv2025

TUB-010, a novel anti-CD30 antibody-drug conjugate based on Tub-tag technology, widens the therapeutic window by reducing toxicity while maintaining high efficacy

TUB-010 is a next-generation antibody-drug conjugate (ADC) targeting CD30, which is expressed on various hematopoietic malignancies such as Hodgkin lymphoma and anaplastic large cell lymphoma. Patients with refractory and relapsed CD30-positive cancers often lack effective and tolerable therapy options. Among the therapeutic options for these patients is brentuximab vedotin (Adcetris), a monomethyl auristatin E (MMAE)-delivering anti-CD30 ADC with a mean drug-to antibody ratio (DAR) of 4. Adcetris exhibits a high response rate at the cost of significant toxicities, among which neutropenia and peripheral neuropathy are the most prevalent adverse events, which are likely driven by the payload MMAE and instability of the maleimide conjugation chemistry. TUB-010 uses the same antibody brentuximab and payload MMAE as Adcetris, but instead of maleimide chemistry, TUB-010 is based on the Tub-tag conjugation strategy, which enables the generation of a homogenous and site-specific DAR 2 ADC with unique biophysical properties. This new technology stably attaches MMAE to the hydrophilic Tub-tag peptides on the light chains via chemoenzymatic conjugation using the enzyme tubulin tyrosine ligase. TUB-010 demonstrates similar binding affinity, internalization and lysosomal release characteristics as Adcetris in CD30-positive cells. When normalized to the MMAE concentration, TUB-010 shows comparable in vitro cytotoxic efficacy as well as similar bystander activity compared to Adcetris on established cancer cell lines. Importantly, TUB-010 exhibits higher stability with neglectable premature deconjugation in circulation and reduced high molecular weight species formation as well as lower non-specific cytotoxicity on target-negative cells compared to Adcetris. As a consequence, TUB-010 induces superior tumor control compared to Adcetris when dosed at equal MMAE concentrations in vivo and also shows lower toxicity and higher tolerability in rodents and non-human primates. Taken together, TUB-010 is a novel and potential best-in-class anti-CD30 ADC with improved biophysical properties designed to deliver the cytotoxic payload with higher precision and with a wider therapeutic window than Adcetris using Tub-tag conjugation technology. Therefore, TUB-010 may increase the clinical benefit of ADC therapies for patients with CD30-positive malignancies.

cancer biology↗

bioRxiv2023

Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Efforts to improve the anti-tumor response to KRASG12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.

cancer biology↗

bioRxiv2020

Information-theory-based benchmarking and feature selection algorithm improve cell type annotation and reproducibility of single cell RNA-seq data analysis pipelines

Single cell RNA sequencing (scRNA-seq) data are now routinely generated in experimental practice because of their promise to enable the quantitative study of biological processes at the single cell level. However, cell type and cell state annotations remain an important computational challenge in analyzing scRNA-seq data. Here, we report on the development of a benchmark dataset where reference annotations are generated independently from transcriptomic measurements. We used this benchmark to systematically investigate the impact on labelling accuracy of different approaches to feature selection, of different clustering algorithms, and of different sets of parameter values. We show that an approach grounded on information theory can provide a general, reliable, and accurate process for discarding uninformative features and to optimize cluster resolution in single cell RNA-seq data analysis.

bioinformatics↗

bioRxiv2020

HIF2α is a Direct Regulator of Neutrophil Motility

Orchestrated recruitment of neutrophils to inflamed tissue is essential during initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it is still unclear how these factors influence the migration of neutrophils to and at the site of inflammation either during their transmigration through the blood-endothelial cell barrier, or their motility in the interstitial space. Here, we reveal that activation of the Hypoxia Inducible Factor-2 (HIF2) due to deficiency of HIF-prolyl hydroxylase domain protein-2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in models of acute local inflammation. Using systematic RNAseq analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2-dependent neutrophil motility. Thus, we propose that the here identified novel PHD2-HIF2-RhoA axis is vital to the initial stages of inflammation as it promotes neutrophil movement through highly confined tissue landscapes.

immunology↗