Biology subjects

Eberlein, C.

Publications and source records attributed to Eberlein, C..

3 recordsLinked to original sources

bioRxiv2022

Development of a bispecific Antibody Drug Conjugate targeting CD7 and CD33 to treat Acute Myeloid Leukaemia

Acute myeloid leukemia (AML) is a heterogeneous malignancy of the bone marrow associated with poor outcomes and limited treatment options available to patients. Recent developments have demonstrated that patient stratification based on disease classification (e.g. somatic mutations) allows for selective treatment regimens and greatly improved outcomes. AML patients can also be stratified based upon the heterogeneous immunophenotype of surface antigen expression on leukemic blasts and stem cells. Here we present data identifying a sub-population of AML patients showing expression of both CD33 and CD7 on their tumour cells, using mass cytometry. This combination of antigens is disease-specific, and is not expressed on healthy haematopoietic cells in patients. We developed a bispecific antibody-drug conjugate (ADC) targeting both CD7 and CD33 and demonstrate that these bispecific ADCs are cytotoxic to AML cells in vitro. Importantly, the anti-CD33/CD7 bispecific ADCs are more selective than single-antigen targeting ADCs and safely discriminate tumour from healthy cells (either myeloid or lymphoid). These anti-CD33/CD7 bispecific ADCs are well tolerated and selectively target AML cells in pre-clinical in vivo studies in mice. This study presents the first proof-of-principle for targeting specific and unique combinations of surface antigens on tumour cells with potential to overcome observed toxicities with current ADCs.

cancer biology↗

bioRxiv2021

Different trajectories of polyploidization shape the genomic landscape of the Brettanomyces bruxellensis yeast species

Polyploidization events are observed across the tree of life and occurred in many fungi, plant and animal species. Polyploidy is thought to be an important source of speciation and tumorigenesis. However, the origins of polyploid populations are not always clear and little is known about the precise nature and structure of their complex genome. Using a long-read sequencing strategy, we sequenced a large number of isolates from the Brettanomyces bruxellensis yeast species, which is found in anthropized environments (e.g. beer, contaminant of wine, kombucha and ethanol production) and characterized by several polyploid subpopulations. To reconstruct the polyploid genomes, we phased them by using different strategies and we found that each subpopulation had a unique polyploidization history with distinct trajectories. The polyploid genomes contain either genetically closely related (with a genetic divergence < 1%) or diverged copies (> 3%), indicating auto- as well as allopolyploidization events. These latest events have occurred independently with a specific and unique donor in each of the polyploid subpopulations, and exclude the known Brettanomyces sister species as possible donors. Finally, loss of heterozygosity events have shaped the structure of these polyploid genomes and underline their dynamic. Overall, our study highlights the multiplicity of the trajectories leading to polyploid genomes within a same species.

genomics↗

bioRxiv2019

The role of structural pleiotropy and regulatory evolution in the retention of heteromers of paralogs

Many paralogs derive from the duplication of genes encoding homomeric proteins. Such duplication events lead to the formation of homomers and heteromers, thus creating new structures from a single event. We exhaustively characterize this phenomenon using the budding yeast protein-protein interaction network. We observe that paralogs that heteromerize are very frequent and less functionally diverged than those that lost this property, raising the possibility that heteromerization prevents functional divergence. Using in silico evolution, we show that for homomers and heteromers that share binding interfaces, mutations on one complex have pleiotropic effects on the other complex, resulting in highly correlated responses to selection. As a result, heteromerization could be preserved indirectly due to selection for the maintenance of homomers. By integrating data on gene expression and protein localization, we find that regulatory evolution could play a role in overcoming these structural pleiotropic effects and in allowing paralog functional divergence.

evolutionary biology↗